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Background: Short-chain fatty acids have been reported to have anti-inflammatory and antioxidant functions; whether isobutyrate, a short-chain fatty acid, is protective against liver injury in a dextran sodium sulfate (DSS)-induced colitis and its molecular mechanism is unknown. In this study, DSS was used to induce a liver injury from a colitis model in piglets, which was expected to prevent and alleviate DSS-induced liver injury by feeding sodium isobutyrate in advance., Results: The results showed that sodium isobutyrate could restore DSS-induced histopathological changes in the liver, inhibit the activation of the toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa-B signaling pathway, and then reduce the DSS-induced release of pro-inflammatory cytokines tumor necrosis factor-α, interleukin 1β, and interleukin 6, reducing inflammatory response. Moreover, we found that sodium isobutyrate could play an antioxidant and apoptosis-reducing role by maintaining reduced mitochondrial function., Conclusion: In conclusion, sodium isobutyrate has a preventive and protective effect on liver injury in a DSS-induced colitis. There is a potential application prospect for it in treating ulcerative-colitis-induced liver injuries. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Ethnopharmacological Relevance: Triptolide (TP) is an abietane-type diterpenoid isolated from the traditional Chinese herb Tripterygium wilfordii Hook. F, which is used to relieve rheumatism, alleviate joint pain and swelling, and promote blood circulation for more than 600 years in China. The most common preparations containing TP from Tripterygium wilfordii Hook F, which are Tripterygium tablets and Tripterygium glycoside tablets, are widely used in clinical for treating rheumatoid arthritis and other autoimmune diseases at present. However, the clinical application is hindered by severe systemic toxicity induced by TP, especially hepatotoxicity. It is crucial to discover potent and specific detoxification strategy for TP., Aim of Study: According to our previous study, TP-induced hepatotoxicity is primarily related to macrophages. This study aimed to investigate the alleviation effects of macrophage depletion on the TP-induced liver injury in mice and to explore the related mechanisms by integration of metabolomics and proteomics., Materials and Methods: Mice were treated with clodronate liposomes to deplete macrophage before administration of triptolide. The alleviation effects were evaluated by biochemical analysis of serum and histopathology observation of the hepatic tissues. Metabolomics and proteomics were carried out to explore the mechanism of macrophage depletion on triptolide-induced liver injury. The levels of mRNA and protein of TLR4- MyD88-NF-κB axis were further detected., Results: The altered levels of biochemistry indicators, including aminotransferase (ALT) and aspartate aminotransferase (AST), albumin (ALB), and γ-glutamyltranspeptidase (GGT) were significantly recovered, and histopathological liver injury also showed restoring tendency in mice with macrophage depletion compared to mice with TP-treatment. The inflammation indicator interleukin-6 (IL-6) and interleukin-1β (IL-1β) were recovered significantly after depletion of macrophage. Results of metabolomics and proteomics demonstrated that macrophage depletion exerted protective effects on triptolide-induced liver injury by regulating 85 metabolites and 202 proteins. Joint analysis of multi-omics data suggested macrophage depletion could regulate lipid metabolism and maintain inflammatory homeostasis. The increased expression of NF-κB, TLR4, and MyD88 were decreased after depletion of macrophage., Conclusion: TP-induced hepatotoxicity is mainly associated with dysfunction of macrophages and imbalance of inflammatory homeostasis. The findings of this study may help facilitate the development of novel therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: Methylcinnamate (MC), a safe flavoring agent naturally found in Occimum basilicum L. is reported to have an anti-inflammatory responses in various disease models. Acetaminophen (APAP) toxicity is a significant contributor to acute liver injury, which leads to oxidative stress and inflammation. The transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulated the cellular defense mechanisms aid to antioxidant response facilitation and reduction in inflammation against various disorders., Methodology: This study evaluated the protective effects of MC in APAP-induced hepatotoxicity in mice and its anti-oxidant, anti-inflammatory, and Nrf2 mechanisms were studied. In-vitro 2,2-diphenyl-1-picrylhydrazyl assay showed the antioxidant capacity of MC. Mice were pretreated with MC (25, 50, 75, and 100 mg/kg) orally for 7 days. After a fasting period of 16 h, hepatotoxicity was induced by injecting APAP 300 mg/kg intraperitoneal on day 7. Liver profile, oxidative test, and histopathological changes were studied. Gene expression of interlukin-1β (IL-1β), interlukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), cytochrome P450 2E1 (CYP2E1), Nrf2, and NAD(P)H dehydrogenase (quinone) 1 (NQO-1) were estimated by real time quantitative polymerase chain reaction (RT-qPCR). IL-1β, IL-6, and TNF-α concentrations were also analyzed by enzyme-linked immunosorbent assay (ELISA)., Results: The MC treatment showed a notable reduction in alanine transaminase, aspartate aminotransferase and alkaline phosphatase activities, and total bilirubin level of serum. Moreover, MC significantly attenuated oxidative stress by rising the antioxidant enzymes catalase, glutathione, and superoxide dismutase and reducing the malondialdehyde and nitric oxide levels in the liver. Furthermore, MC successfully mitigated the levels of IL-1β, IL-6, and TNF-α, which were estimated through RT-qPCR and ELISA. The RT-qPCR revealed a CYP2E1 enzyme inhibition and significant upregulation of hepatic Nrf2 and NQO-1 levels after MC therapy. Histopathological analysis showed improvement in liver injury within the MC treatment groups., Conclusion: It was concluded from this study that pretreatment of MC had successfully protected the liver through anti-inflammatory, anti-oxidant activity upon subsequent activation of Nrf2., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Lysosomal stress due to the accumulation of nucleic acids (NAs) activates endosomal TLRs in macrophages. Here, we show that lysosomal RNA stress, caused by the lack of RNase T2, induces macrophage accumulation in multiple organs such as the spleen and liver through TLR13 activation by microbiota-derived ribosomal RNAs. TLR13 triggered emergency myelopoiesis, increasing the number of myeloid progenitors in the bone marrow and spleen. Splenic macrophages continued to proliferate and mature into macrophages expressing the anti-inflammatory cytokine IL-10. In the liver, TLR13 activated monocytes/macrophages to proliferate and mature into monocyte-derived KCs (moKCs), in which, the liver X receptor (LXR) was activated. In accumulated moKCs, tissue clearance genes such as MerTK, AXL, and apoptosis inhibitor of macrophage (AIM) were highly expressed, while TLR-dependent production of proinflammatory cytokines was impaired. Consequently, Rnaset2-/- mice were resistant to acute liver injuries elicited by acetaminophen (APAP) and LPS with D-galactosamine. These findings suggest that TLR13 activated by lysosomal RNA stress promotes the replenishment of tissue-protective Kupffer cells., (© 2025 Sato et al.)

Aflatoxin B1 (AFB1) is a prevalent contaminant in food and feed matrices, known for its hepatotoxic effects. Its metabolic breakdown generates reactive oxygen species (ROS), leading to oxidative stress and subsequent liver damage. Mitigating oxidative stress is, therefore, essential for ameliorating the hepatocellular damage and systemic toxicity caused by AFB1. Here, we synthesized arginine carbon dots (Arg-CDs) with robust antioxidant properties through a simple hydrothermal method using arginine and citric acid. Our investigation demonstrated that Arg-CDs effectively mitigate oxidative stress in nematodes. Furthermore, in murine models of AFB1-induced hepatic injury, Arg-CDs effectively restored liver function, as evidenced by the improvement in histopathological features and biochemical markers. Notably, Arg-CDs administration upregulated the transcriptional activity of nuclear factor erythroid 2-related factor 2 (Nrf2), along with its downstream antioxidant effectors and phase II detoxifying enzymes under AFB1 exposure. Moreover, Arg-CDs alleviated hepatic inflammatory injury by modulating the NLRP3/Caspase-1/GSDMD-mediated pyroptosis pathway. Arg-CDs also demonstrated therapeutic potential in enhancing intestinal barrier function in AFB1-exposed mice. Collectively, these findings highlight the potential of Arg-CDs as a novel and biocompatible therapeutic modality for alleviating AFB1-induced hepatic and intestinal damage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Citrinin (Cit) is a metabolite of Monascus Aspergillus that is known to be nephrotoxic and affects the safety of Monascus products. Here, we investigated the effects of an intervention with bioactive Polygonatum sibiricum polysaccharides (PSPS) on Cit-induced toxic damage in populations with dietary patterns characterized by alcohol consumption. Our results showed that the PSPS intervention significantly increased the levels of intestinal Cit and its metabolite M1. Additionally, the PSPS intervention mitigated intestinal damage, as well as liver and kidney stress, and flora disruption induced by combined exposure to Cit and alcohol. It also promoted the recovery of Lactobacillus abundance. However, there was no significant improvement in hippocampal damage. Metabolomics analysis indicated that the PSPS significantly influenced the metabolic pathways involved in energy metabolism in liver and kidney, such as aspartic acid and tyrosine metabolism. Correlation analysis revealed a significant relationship between the reduction of Cit metabolites and the differential metabolites in the liver and kidney. Our results demonstrated that the PSPS intervention showed promise in improving intestinal flora imbalances, enhancing the barrier function against Cit, alleviating intestinal, liver, and kidney damage, and addressing the metabolic disorders along the gut-liver-kidney axis resulting from the co-exposure to Cit and alcohol., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Aim: Tramadol (TRM), a widely used opioid analgesic for moderate to severe pain, is associated with liver and kidney toxicity at high doses or prolonged use. This study investigates the protective role of rosmarinic acid (RA), a natural phenolic compound known for its antioxidant, anti-inflammatory, and cell-protective properties, against TRM-induced hepatorenal toxicity., Methods: Thirty-five male Wistar rats were divided into five groups: Control, TRM, RA, TRM + RA25, and TRM + RA50. Rats received TRM (50 mg/kg) and RA (25 or 50 mg/kg), with liver and kidney function tests, oxidative stress, inflammation, ER stress, apoptosis, and tissue damage indicators assessed through qRT-PCR, ELISA, Western blotting, H&E, and immunohistochemical analysis., Results: TRM induced liver and kidney dysfunctions, evident from increased ALT, AST, ALP, urea, creatinine, nephrin, TIM-1 and 8-OHdG levels, along with activated oxidative stress, inflammation, ER stress, and apoptosis pathways. RA significantly reduced these effects, ameliorating histologic and immunohistochemical markers of tissue damage and inflammation., Conclusion: RA demonstrates therapeutic potential by mitigating TRM-induced hepatorenal toxicity and preserving tissue integrity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Methylmercury (MeHg) is a potent hepatotoxin with a complex mechanism of inducing liver injury. Ferroptosis, an iron-dependent form of non-apoptotic cell death, is implicated in various toxicological responses, but its role in MeHg-induced liver damage remains under investigation. In this study, we established an acute liver injury (ALI) model in mice via gavage of MeHg (0, 40, 80, 160 μmol/kg). Histopathological analysis revealed dose-dependent liver damage, corroborated by elevated serum biochemical markers, confirming MeHg-induced hepatotoxicity. MeHg exposure raised MDA levels, inhibited SOD and GSH activity, and downregulated CAT expression. Increased iron accumulation and elevated transferrin receptor expression were observed, alongside decreased GPX4 and SLC7A11 levels, indicating ferroptosis involvement. Additionally, inflammation in MeHg-exposed livers was markedly intensified, as evidenced by increased MPO activity, upregulation of pro-inflammatory cytokines, and activation of the NF-κB/NLRP3 signaling pathway. The Keap1/NRF2/HO-1 oxidative stress response pathway was significantly activated, and p38/ERK1/2 MAPK signaling was notably increased. These findings suggested that MeHg induced acute liver injury through the interplay of ferroptosis, oxidative stress, inflammation, and MAPK signaling pathways, providing a scientific basis for future exploration of the mechanisms underlying MeHg-induced hepatotoxicity and potential therapeutic strategies., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Ubiquitin-specific protease 53 (USP53) deficiency is associated with familial intrahepatic cholestasis in which serum gamma-glutamyl transferase (GGT) activity is relatively low. However, how USP53 deficiency contributes to cholestasis is obscure. No animal model has been reported., Methods: Usp53 liver-specific knockout (Usp53 cKO) mice generated by crossing Usp53 fl/fl mice with albumin-cre (Alb-cre) recombinase transgenic mice were challenged with dietary cholic acid (CA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). General well-being, hepatobiliary-injury biomarker values, histopathologic and ultrastructural appearances, and expression of key genes were compared with those in wild-type (WT) littermates. Interactions of USP53 and TJP2 were investigated by immunofluorescence and co-immunoprecipitation., Results: Usp53 cKO mice exhibited no obvious differences from WT mice when fed with either normal-chow or CA-added diet. However, after 4 weeks of DDC feeding, Usp53 cKO mice lost less weight, were less icteric, had more nearly normal biomarker values, and accumulated less intrahepatic pigment than WT mice. On normal chow, mRNA expression of critical hepatic transporters Abcb11, Ntcp, and Abcc2 was lower in Usp53 cKO liver than in WT liver; after DDC feeding, mRNA expression of Tjp2 was higher, while detoxification enzymes Cyp3a11, Cyp2b10, and Sult2a1 was lower in Usp53 cKO liver than in WT liver, and hepatocellular tight junctions were significantly longer. USP53 interacts with TJP2., Conclusions: Usp53 deficiency can protect mice from DDC-induced liver injury. Liver Usp53 cKO causes upregulation of hepatobiliary Tjp2, with biochemical and histologic features that largely mimic those of liver Tjp2 cKO, implying that USP53 deficiency may share similar mechanism to TJP2 deficiency., Competing Interests: Declaration of competing interest The authors have nothing to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Drug-induced liver injury (DILI) has emerged as among of the undesirable drug effects, posing significant threats to human health. However, in clinical practice, there remains a shortage of dependable and pre-diagnosis tools for DILI. Numerous studies indicated that the elevated intrahepatic viscosity levels were closely linked to the onset and progression of DILI. Therefore, establishing reliable tools to monitor mitochondrial viscosity are crucial for prompt diagnosis of DILI in situ. Herein, we proposed a new near-infrared (NIR) fluorescence probe (Wyry-M-V) for detecting mitochondrial viscosity, in which consisted of xanthene, multiple viscosity-responsive rotors (diphenyl, vinyl cyanide, and benzyl chloride) and mitochondrial targeting site (pyridinium cation). Furthermore, the Wyry-M-V was triumphantly utilized in mitochondrial viscosity imaging upon treatment with lipopolysaccharide, nystatin and acetaminophen (APAP). Notably, based on the advantages of NIR emission wavelength, the Wyry-M-V was resoundingly used for the detection of mitochondrial viscosity in APAP-induced DILI mice model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The emergence of cuproptosis, a novel form of regulated cell death, is induced by an excess of copper ions and has been associated with the progression of multiple diseases, including liver injury, cardiovascular disease, and neurodegenerative disorders. However, there are currently no inhibitors available for targeting specific cuproptosis-related pathways in therapy. Here, the compound merestinib (MTB) has been identified as a strong inhibitor of cuproptosis through screening of a kinase inhibitor library. The results show that MTB effectively blocks elesclomol-CuCl 2 (ES-Cu) induced cuproptosis by preventing the aggregation of lipoylated proteins and the destabilization of Fe-S cluster proteins, thereby preventing proteotoxic stress and ultimately cell death. Mechanistically, MTB decreases oxidative stress levels by binding directly to NRF2. Additionally, it boosts the efficiency of the copper homeostasis and facilitates the exocytosis and transportation of copper ions, ultimately inhibiting cuproptosis. Furthermore, our research showed that MTB has the ability to alleviate cuproptosis-driven acute liver injury in mice. These findings suggest that MTB is a specific inhibitor of cuproptosis, presenting a hopeful option for therapeutic approaches in cuproptosis-related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Given the lack of accurate diagnostic methods of acetaminophen (APAP)-induced acute liver failure (ALF), the search for new biomarkers for its diagnosis is an urgent need. The aim of this study was to evaluate the role of bone morphogenetic protein 6 (BMP6) in APAP-induced ALF progression and its potential value as a biomarker of ALF. Hepatic and circulating BMP6 expression was assessed in APAP-treated mice and in serum samples from patients with APAP overdose. In addition, BMP6 expression and release was evaluated in hepatocytes after APAP exposure. BMP6 gene was silenced in Huh7 cells prior to APAP treatment and the culture medium (CM) was added to THP1 cells to evaluate the paracrine effects of hepatocyte BMP6 on APAP toxicity. Hepatic and serum BMP6 levels were increased in mice after APAP-induced ALF. In addition, a positive correlation was observed between circulating BMP6 and ALT activity in patients exposed to APAP overdose. Moreover, hepatocytes expressed and released BMP6 to the CM after APAP treatment. Indeed, the CM from APAP-treated Huh7 cells upregulated M1 and M2 markers in THP1 monocytes. The CM from BMP6-silenced Huh7, which was depleted of BMP6, reduced the expression of M2 markers in THP1 cells. In fact, expression of M2 markers was increased in THP1 cells exposed to BMP6. This study reveals that hepatic BMP6 expression is increased in APAP-induced acute liver injury, positioning it as a potential new biomarker of liver damage severity. Moreover, our data indicate that BMP6 might play a role in the hepatocyte-macrophage crosstalk during APAP-induced hepatotoxicity., Competing Interests: Declarations. Conflict of interest: All authors have declared that no competing interest exists., (© 2025. The Author(s).)

The present study aimed to investigate the impact of Sparassis latifolia polysaccharides (SLPs) on hepatic immune function in cyclophosphamide (CTX)-induced immunocompromised mice. Our findings demonstrated that SLPs effectively suppressed the production of alanine aminotransferase (ALT), aspartate aminotransferase (AST), inflammatory factors, and acute phase proteins, while improving the hepatic oxidative stress state. Additionally, SLPs exerted inhibitory effects on inflammatory cell infiltration within hepatic tissue. Transcriptomic results revealed that 246 differentially-expressed genes (DEGs) were identified. Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis showed that the more DEGs in SLPs group were mainly related to immune signal transduction and metabolism pathways. And more DEGs were mainly related to MAPK signaling pathway and JAK/STAT signaling pathway. Metabolome analysis demonstrated that SLPs significantly modulated specific metabolites in the liver, including lipids and lipid-like molecules, organic acids and their derivatives, organic heterocyclic compounds, phenylpropanoids and polyketones, organic oxygenates, and benzene. The comprehensive analysis of transcriptome and metabonomics revealed the activation of immune-related signal pathways in mice liver stimulated by CTX. Notably, the involvement of diverse genes and metabolites was observed in the metabolism of arachidonic acid (AA) and JAK/STAT pathway. Correlation analysis also showed that there was a certain correlation between metabolites and differential genes. The present findings offer novel insights into the regulatory mechanism of liver immune injury by SLPs, which exhibits potential application value in improving immunocompromised populations., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Acetaminophen-induced acute liver injury (AILI) is one of the common causes of abrupt liver failure in numerous nations. Several previous studies revealed that tiliroside, a glycoside flavonoid, exerts neuroprotective and renal protective effects. However, whether it has hepatoprotective effects is not known. The objective of this research is to examine whether tiliroside can protect against AILI., Methods: AILI mouse and cell models were performed to evaluate the protective effects of tiliroside. Molecular docking, cellular thermal shift assay, immunoprecipitation, and RNA-seq were performed to analyze the possible mechanisms of tiliroside., Results: In vivo, tiliroside attenuated AILI in mice significantly, as evidenced by lower ALT and AST levels. Molecular docking, cellular thermal shift assay, and RNA-seq analysis revealed that tiliroside promoted the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the expression of its downstream genes through disruption of the NRF2-KEAP1 protein-protein interaction to inhibit KEAP1-mediated ubiquitination and degradation of NRF2, thereby inhibiting oxidative stress in the livers of AILI mice. Furthermore, hepatocyte-specific knockout of NRF2 greatly attenuated the hepatic-protective effects of tiliroside in mice. In vitro, tiliroside protected against acetaminophen-induced oxidative stress on cultured hepatocytes through activation of NRF2. In addition, NRF2 knockout markedly blunted the protection effects of tiliroside, suggesting that NRF2 mediates the hepatic-protective effects of tiliroside., Conclusions: Our study demonstrated that tiliroside could protect against AILI by activating the KEAP1/NRF2 pathway, which primarily inhibits the processing of oxidative stress and cell death. Our results suggest that tiliroside could serve as a potential agent for the clinical treatment of AILI., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Gardeniae fructus (GF) is a widely used traditional Chinese medicine; however, its application is limited due to the hepatotoxicity of its main active component, Geniposide (GE). To investigate the material basis and mechanisms of GE-induced hepatotoxicity. We utilized an in vitro gastrointestinal model to examine metabolic processes, conducted in vivo experiments to study GE's hepatotoxic effects and performed cellular experiments to verify toxic effects. Results indicated that GE-induced hepatotoxicity is associated with its metabolite Genipin (GP), with GP's hemiacetal structure being a key factor. Upon exposure of the C-1 hydroxyl group of GP, a covalent binding reaction occurs with amino acids. This reaction readily proceeds as a phase II conjugation with the amino group of lysine (LYS), resulting in the formation of genipin-lysine (GP-LYS) adducts. These adducts affect cellular oxidative stress and trigger cascading reactions leading to hepatotoxicity. Our findings not only highlight chemical structure as a crucial factor influencing toxicity but also advance the understanding of GE's toxic action mechanism. This study provides a foundation for guiding rational clinical use of GE and offers valuable insights for the development of novel GE-based pharmaceuticals., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Wensheng zhang reports financial support was provided by Beijing Normal University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Doxorubicin (DOXO) is a powerful anthracycline chemotherapeutic drug, but its clinical usage has been limited by its deleterious effects on different organs, particularly hepatotoxicity. The aim of this study was to establish the combined effects of aerobic interval training (AIT) and curcumin supplementation on mitigating oxidative damage and endoplasmic reticulum (ER) stress-mediated apoptosis in a rat model of DOXO-induced hepatotoxicity. Fifty-six male Sprague-Dawley rats were randomly split into six groups: control (CON), vehicle, doxorubicin (Dox), doxorubicin + curcumin (Dox-C), doxorubicin + AIT (Dox-A), and doxorubicin + curcumin + AIT (Dox-AC). DOXO was intraperitoneally injected weekly (4 mg/kg/week) for five weeks. Curcumin supplementation (100 mg/kg/day) and AIT (4 min at 80-90% of VO 2max intermitted by 3 min of active rest at 65-75% of VO 2max ) were conducted five times a week for six weeks. Finally, the hepatic tissue and blood samples were collected to assess histopathological changes, liver damage biomarkers, and the protein expression of oxidative stress, ER stress, and apoptosis markers. Tissue sections revealed that AIT and curcumin supplementation significantly improved hepatotoxicity induced by DOXO, as evidenced by the positive effects on histopathological alterations and serum markers of hepatic damage (P < 0.05). Both curcumin and AIT significantly reduced DOXO-triggered oxidative damage, ER stress, and apoptosis (P < 0.05), with the latter showing slightly higher effectiveness. Consequently, the combination of AIT with curcumin supplementation exhibits protective effects against chronic hepatotoxicity induced by DOXO, with AIT demonstrating relatively greater efficacy in increasing antioxidant capacity and reducing ER stress and apoptosis., Competing Interests: Declaration. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Methotrexate (MTX) has been used in high doses for cancer therapy and low doses for autoimmune diseases. It is proven that methotrexate-induced hepatotoxicity occurs even at relatively low doses. It is known that garden cress has anti-inflammatory, antioxidant, and hepatoprotective properties. This study investigates the potential alleviating effect of garden cress oil (GCO) against MTX-induced hepatotoxicity in rats. The chemical composition of GCO was assessed using GC/MS analysis. Liver damage was studied using hepatotoxicity biomarkers, molecular, and histological analysis. Also, the effects of GCO on TNF-α and caspase-3 proteins were evaluated through molecular docking studies. The results demonstrated that MTX caused liver damage, as seen by elevated levels of the liver enzymes ALT, AST, and ALP. Likewise, MTX showed clear signs of apoptosis, such as increased mRNA expression levels of BAX, Caspase-3, and P53, and increased liver inflammation indicated by higher levels of TNF-α expression. MTX exhibited significant liver damage, as demonstrated by histological examination. Treatment with GCO effectively alleviated the apoptotic effects of MTX, provided protection against inflammation, and restored histological alterations. GC/MS metabolite profiling of garden cress oil revealed the presence of several phytoconstituents, including tocopherols, erucic acid, sesamolin, linoleic acid, vaccenic acid, oleic acid, stearic acid, and palmitic acid, that showed strong binding affinities toward TNF-α and caspase-3 proteins in molecular docking studies, which could explain the anti-apoptotic and anti-inflammatory potential of GCO., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval: The animal experiments were approved by the Ethics Committee of the National Research Centre (Approval No. 09410125)., (© 2025. The Author(s).)

Scopoleitin (SP), a bioactive compound from many edible plants and fruits, exerts a wide range of biological activities, however the role and mechanism of SP in acetaminophen (APAP)-induced hepatotoxicity remains unclear. In this study, we verified the protective effect of SP on APAP-induced liver injury (AILI) hepatotoxicity and explore the underlying molecular mechanisms. Here, we showed that SP alleviated AILI by reducing serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, hepatic histopathological damage, inflammation, and liver cell apoptosis. In addition, SP attenuated the accumulation of malondialdehyde (MDA) and exhaustion of glutathione (GSH) levels and increased the superoxide dismutase (SOD) levels induced by APAP. Consistently, SP significantly reduced the gene transcription of cytochrome P450 (CYP)2E1, CYP1A2, and CYP3A11 in the livers of mice induced by APAP. Moreover, SP pretreatment effectively promoted the expression of Nrf2, Keap1, and its signal downstream HO-1, NQO1, GCLc, and GCLm, suggesting the activation of the Nrf2 signaling pathway. SP inhibited APAP-induced hepatocyte apoptosis by regulating the protein levels of apoptosis-related proteins (cytochrome C, Bax, Caspase-3, Bcl2, and PARP). SP suppressed APAP-induced expression of NLRP3 and reduced the levels of proinflammatory factors, including tumor necrosis factor-alpha (TNF-α), F4/80, Caspase-1, and interleukin (IL)-1 beta (IL-1β). Moreover, SP downregulated APAP-induced high-mobility group box 1 (HMGB1) and toll-like receptor 4 (TLR4) expression, inhibited nuclear factor kappa-B (NF-κB) and MAPK activation. Taken together, our study reveals the protective roles of SP against AILI through the downregulation of NLRP3 expression, and the inhibition of the Nrf2/HMGB1/TLR4/NF-κB signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Callistephus chinensis Nees is an herbaceous plant in the Asteraceae family that has various traditional effects, especially in preventing liver disease. Callistephus A (CA) is a sesquiterpene compound with a rare 6/7 ring skeleton, which has been isolated only from the Callistephus chinensis Nees, but whether CA protects the liver is unknown. Immunological liver injury (ILI) is a common liver disease mediated by the immune system. Therefore, this study investigated whether CA had a protective effect on ILI and uncovered its molecular mechanisms. To study the impact, target, and signal pathway of CA in preventing ILI, we hope to find active components from plants to avoid ILI. In this study, CA regulated the differentiation balance of CD4 + T cells (Th1/Th2 and Th17/Treg balance) and the secretion of inflammatory factors (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interferon-gamma (IFN-γ), interleukin-4 (IL-4), interleukin-17A (IL-17A) and transforming growth factor-β (TGF-β). CA improves liver inflammation by regulating IFN-γ-induced JAK/STAT1 signaling pathways. CA reduced hepatocyte apoptosis by decreasing protein expression of BCL2-associated X (Bax), cleaved caspase-3, and cleaved Poly (ADP-ribose) polymerase 1 (PARP-1), but increased Bcl-2 protein expression, which was achieved by regulating the MAPK pathway. To investigate the role of CA in immune liver injury, we performed in vitro cell experiments using alpha mouse liver 12 (AML12) cells. The cell experiments showed that CA potently inhibited LPS-mediated AML12 cell damage. After adding CA, damaged mitochondria are cleared through mitochondrial autophagy and reduced production of intracellular reactive oxygen species (ROS). Finally, molecular docking results showed that CA had a strong affinity for five essential target proteins (JAK1, JAK2, STAT1, JNK, and p38). CA regulates the differentiation, anti-inflammatory, and anti-apoptosis of CD4 + T cells. The mechanism of CA against ILI is related to inhibiting the activation of JAK/STAT1 and MAPK signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

2-Amino-3-methylimidazole [4,5- f ] quinoline (IQ) is a kind of heterocyclic amine (HCAs) with high carcinogenicity in hot processed meat. Rutin (Ru) is a flavonoid compound with anti-inflammatory and antioxidant properties. However, whether Ru is scatheless under IQ-stimulated potential unhealthy conditions, especially liver function, in vivo, is unknown. In this study, we explored the effects and underlying mechanism of Ru on liver injury induced by a low dose of IQ in mice. Results showed that Ru supplement led to liver injury upon low-dose IQ alone administration, as shown by histological analysis, inflammatory, and serum biochemical indexes. Additionally, nontargeted metabolomics analysis revealed that coexposure of Ru and IQ disrupted liver metabolic balance, leading to significant changes in metabolites and metabolic pathways, hinting at a possible relationship with intestinal microbiota. Furthermore, the 16S rRNA sequencing data indicated that a combination of Ru and IQ caused gut microbiota dysbiosis and decreased the level of short-chain fatty acids (SCFAs). Correlation analysis between gut microbiota, SCFAs, liver metabolites, and liver damage markers highlighted the crucial role of the gut-liver axis in IQ and Ru coexposure-induced liver injury in vivo. In general, this study offers a valuable perspective on flavones and HCA compounds in the realms of food safety and human health.

Lipopolysaccharide (LPS) exacerbates liver injury by activating various inflammatory pathways. Clusterin, a glycoprotein involved in lipid transport, and cytoprotection, is known to have inhibitory effects on liver steatosis and fibrosis. In this study, we investigated the role of clusterin in regulating LPS-induced liver injury and its effects on liver injury in C57BL/6 mice and clusterin knockout mice injected with LPS for 3 h. Primary Kupffer cells (KCs) and hepatocytes (HCs) were isolated from these mice and examined using immunohistochemistry, real-time RT-PCR, ELISA, and western blot analysis to assess the effects of clusterin. Clusterin deficiency significantly exacerbated LPS-induced liver injury, as evidenced by increased inflammatory cell infiltration, elevated serum alanine aminotransferase and aspartate aminotransferase levels, and upregulated expression of pro-inflammatory cytokines and components of the NLRP3 inflammasome. By contrast, overexpression of clusterin in primary Kupffer cells and hepatocytes significantly reduced these inflammatory markers. Furthermore, the protective mechanism of clusterin involved inhibition of the STAT3 signaling pathway. These findings suggest that clusterin is a useful therapeutic target to modulate cytokine production and key inflammatory signaling pathways in inflammatory liver diseases., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Acetaminophen (APAP) is a commonly utilized antipyretic and analgesic drug. Overdose of APAP is a primary contributor to drug-induced liver injury and acute liver failure (ALF). SW033291 has been shown to play a role in tissue regeneration in various diseases; however, its potential to facilitate liver regeneration following APAP-induced hepatic injury remains unexamined. Thus, this study focused on exploring the therapeutic impacts and mechanisms of SW033291 on liver damage by establishing models of APAP-induced acute liver injury in mice. The results showed that treatment with SW033291 reduces serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, decreases the area of hepatic necrosis, increases glutathione (GSH) levels, and decreases tissue malondialdehyde (MDA) content, as well as the expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in mice with liver injury. It could also promote hepatocyte proliferation and inhibit apoptosis by increasing tissue prostaglandin E2 (PGE2) levels. In conclusion, SW033291 demonstrates the capacity to ameliorate APAP-induced hepatic injury in mice by fostering liver regeneration, attenuating oxidative stress, and modulating inflammatory responses, thereby presenting itself as a promising candidate for the development of therapeutic interventions targeting acute liver failure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Introduction: Ulcerative colitis (UC) is often characterized by dysbiosis of the colonic microbiota and metabolic disturbances, which can lead to liver damage. Patchoulene epoxide (PAO), a tricyclic sesquiterpene derived from the aged essential oil of Pogostemonis Herba, is known for its anti-inflammatory and ulcer-healing properties. However, its dual protective role against UC and liver injury remains largely unexplored. This study aims to elucidate the protective effect and underlying mechanism of PAO against dextran sulfate sodium (DSS)-induced UC and liver injury in mice., Methods: Colitis and liver injury in mice were induced by adding 3% DSS to their drinking water continuously for 7 days, and PAO at the doses of 20 and 40 mg/kg was administered orally to mice daily from the first day until the experimental endpoint. Stool consistency scores, blood stool scores, and body weights were recorded weekly. Disease activity index (DAI) was determined before necropsy, where colon and liver tissues were collected for biochemical analyses. Additionally, the fecal microbiome and its metabolites of treated mice were characterized using 16S rRNA amplicon sequencing and metabolomics., Results: PAO significantly reduced the disease activity index and mitigated colonic atrophy in UC mice. It also improved colonic and hepatic pathological changes by safeguarding tight and adherens junctions, and suppressing the generation of pro-inflammatory cytokines and lipopolysaccharide. These beneficial effects were attributed to PAO's capability to regulate the colonic microbiota and metabolic processes. PAO was found to enhance the diversity of the colonic microbiota and to shift the microbial balance in UC mice. Specifically, it restored the microbiota from an Akkermansia-dominated state, characteristic of UC, to a healthier Muribaculaceae-dominated composition. Furthermore, PAO corrected the colon metabolic disturbance in UC mice by modulating the purine metabolism, notably increasing the abundance of deoxyadenosine, adenosine and guanine in UC mice., Conclusions: The therapeutic effect of PAO on UC and liver injury was mainly attributed to its regulation of colonic microbiota and purine metabolism. These insights emphasize the overall therapeutic benefits of PAO in treating UC and liver injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Chen, Xie, Wang, Zhan, Zhuo, Jiang, Miao, Zhang, Zheng, Liu, He and Liu.)

(1) Liver injury caused by an overdose of acetaminophen (APAP) represents a major public health concern. Paeoniflorin (PF) has been reported to have anti-inflammatory and liver-protective effects, but the underlying mechanisms remain unclear. This study aimed to investigate the effect of PF on the crosstalk between pyroptosis and NETs in AILI. (2) APAP-treated C57BL/6J mice were used to demonstrate the protective effect of PF on liver injury. HepG2 and dHL-60 cells were cultured to study the effects of PF on hepatocyte pyroptosis and neutrophil extracellular traps (NETs) in vitro. Moreover, cell co-culture experiments were performed, and mice were treated with a NETs-depleting agent and hepatocyte pyroptosis inhibitor to investigate the improvement of AILI induced by PF through regulating the crosstalk between hepatocyte pyroptosis and NETs. (3) PF significantly alleviated AILI. Additionally, PF inhibited the expression of pyroptosis-related proteins, high-mobility group box 1 (HMGB1), and NETs-associated proteins in vitro and in vivo. The co-culture experiments demonstrated that PF not only inhibited the NETs triggered by hepatocyte pyroptosis, but also suppressed the hepatocyte pyroptosis induced by NETs. In mice with depleted neutrophils, the level of hepatocyte pyroptosis notably decreased, indicating a diminished impact of PF. Similarly, NETs formation was reduced in mice receiving a pyroptosis inhibitor compared to the APAP group. Compared with DNase I alone, the reduction effect of PF combined with DNase I on serum ALT and AST levels decreased from 46.857% and 39.927% to 44.347% and 33.419%, respectively. Compared with DSF alone, PF combined with DSF reduced the ALT and AST levels from 46.857% and 39.927% to 45.347% and 36.419%, respectively. (4) PF demonstrated therapeutic effects on AILI. Its mechanism involves the regulation of the crosstalk between hepatocyte pyroptosis and NETs. This research substantiates the pharmacological promise of PF as a therapeutic intervention for acute AILI.

Ethnopharmacological Relevance: Argemone mexicana L. (Papaveraceae), a weed that thrives in the tropical and subtropical areas of South and Central America, Mexico, Caribbean Islands and India. In India, it has been used traditionally to treat vesicular calculus, inflammatory conditions, and hepatobiliary disorders., Aim of the Study: The present study was aimed to investigate the hepatoprotective efficacy of A. Mexicana roots in paracetamol (PCM)-induced toxicity rat., Materials and Methods: The methanol extract of A. mexicana (MEAM) root was analyzed using Gas Chromatography-Mass Spectrometry (GC-MS) analysis to identify its compounds. Molecular docking analysis of the compounds was conducted against TGF-β and PPAR-α. The hepatoprotective activity of MEAM (200, 400 mg/kg) was evaluated in PCM (3000 mg/kg) intoxicated rats by measuring serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), total bilirubin (TB), total protein (TP), albumin (ALB), globulin (GLB), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Silymarin (100 mg/kg) was used as reference drug. Oxidative stress biomarkers such as superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and lipid peroxidation (LPO) were investigated using liver homogenate. Additionally, the levels of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and anti-inflammatory cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10) were studied. The results of the study were supported by histopathological examination., Results: GC-MS analysis revealed 163 compounds, from which eleven compounds were selected based on their docking scores against TGF-β and PPAR-α. MEAM (400 mg/kg) demonstrated a remarkable reduction in ALT, AST, ALP, GGT, and LDH in contrast to the PCM intoxicated group. A remarkable decline in TB and GLB, along with an increase in TP and ALB, was observed in the MEAM (400 mg/kg) group compared to the untreated PCM group. Rats receiving MEAM (400 mg/kg) exhibited a noticeable decrease in TC, TG, and LDL-C, along with an increase in HDL-C levels compared to PCM-induced untreated rats. The higher dose of MEAM also resulted in a significant decrease in TNF-α, IL-1β, and IL-6, and an increase in IL-4 and IL-10. Similarly, a notable elevation in SOD, CAT, and GSH, along with a decrease in MDA content, was observed in the group receiving MEAM (400 mg/kg). The histopathological result showed reduction of sinusoidal space and vesicular nuclei, with improvement of hepatocytes at the dose of MEAM (400 mg/kg). In molecular docking study, Eupatilin exhibited the highest docking scores of -10.4 kcal/mol and -9.1 kcal/mol against TGF-β and PPAR-α, respectively., Conclusions: MEAM root at dose of 400 mg/kg exhibited hepatoprotective effect against PCM-induced toxicity rat. Eupatilin might be considered as a potential candidate for the hepatoprotective effect of A. mexicana root., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. All the authors involved in this paper entitled “Hepatoprotective efficacy of Argemone mexicana L. root in paracetamol-induced hepatotoxicity in a rat model” declared no conflict of interest., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Drug-induced liver injury (DILI) is an important and common adverse drug event. Rhododendron molle Flos (RMF), as one of toxic Traditional Chinese medicines (TCMs), holds a prominent position in clinical practice for treating rheumatoid arthritis. However, the toxicity of RMF limits its safe. Most of the concerns are about its rapid neurotoxicity and cardiotoxicity, with less attention paid to its hepatotoxicity, and the mechanism of which is still unclear., Aim of the Study: To reveal the mechanism of RMF-induced hepatotoxicity by bioinformatics and multi-omics., Materials and Methods: Rats were intragastric administered RMF at doses of 0.8 g/kg, 0.4 g/kg, and 0.2 g/kg once daily for 2 weeks. Initially, hepatotoxicity was then evaluated using liver function enzymes, antioxidant enzymes, and histopathology. Subsequently, network toxicology, transcriptomics, and metabolomics were used to identify the genes and metabolites. In addition, molecular docking and Western blot were employed to verify toxic components and key targets., Results: RMF caused abnormal levels of ALT, γ-GT, TBIL, and TBA in the serum of rats, as well as abnormal levels of MDA, GSH-Px, and SOD in the liver, leading to inflammatory infiltration of liver cells, with a dose-dependent manner. RMF disordered the steroid hormone biosynthesis, pyruvate metabolism, fatty acid biosynthesis, and arachidonic acid metabolism. Six key targets were identified- UGT1A6, CYP2E1, ACOT1, ACSL5, CTH, and PKLR, along with their corresponding metabolites, namely 17β-estradiol, estriol, arachidonic acid, octadecanoic acid, and pyruvic acid. The hepatotoxicity could be attributed to five diterpenoid components, including grayanotoxin-III, rhodojaponin (RJ)-I, RJ-II, RJ-III, and RJ-V., Conclusions: This study comprehensively identified the toxic components, upstream targets, and downstream metabolites of RMF-induced liver toxicity, providing a basis for evaluating and monitoring liver function in patients during clinical application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Dioscorea bulbifera L. (DBL) was a traditional Chinese medicine commonly used to treat goitre and cancer. Nevertheless, its clinical application may lead to liver injury. Glycyrrhiza uralensis Fisch. (GRR) was primarily utilized in traditional Chinese medicine for its ability to harmonize various medicines and mitigate the toxic effects of poisonous herbs. However, the role of GRR in mitigating the liver toxicity of DBL has not been established after combination., Aim of the Study: This study aimed to clarify the protective effect of GRR against DBL-induced liver injury in mice and investigate its mechanisms of action., Materials and Methods: 75% ethanol was employed to extract DBL and GRR. The extracted components were characterized using LC-MS. Mice were orally gavaged with extracts from each group for 30 days. After the experiment, the pathological changes in the liver of mice were evaluated. Additionally, biochemical markers associated with liver injury were assessed. The primary mechanisms through which GRR mitigates DBL-induced liver injury and the modulation of the liver-intestinal axis by GRR were explored utilizing untargeted metabolomics, targeted BAs metabolomics and 16S rDNA analyses. Furthermore, Western blot and qPCR assessed the protein and mRNA transcription of the farnesoid X receptor (FXR) and nuclear factor-erythroid 2-related factor 2 (Nrf2) as well as BA-related transporters., Results: GRR dose-dependently attenuated DBL-induced liver injury in mice. It mitigated hepatic pathological changes and alleviated hepatic inflammation and oxidative stress. GRR improved metabolic disorders induced by DBL in mice at the metabolite level, focusing on the ABC transporter. Moreover, GRR may be attributed to its activation of FXR/Nrf2 expression, reduction of cholesterol 7-alpha hydroxylase (CYP7A1) expression, promotion of bile salt export pump (BSEP), multi-drug resistance protein 2 (MRP2), P-glycoprotein (P-gp) and sodium taurocholate cotransport polypeptide (NTCP) expression, reduction of bile acid (BA) synthesis, promotion of BA efflux and reabsorption, and improvement of BA metabolic disorders. In addition, GRR ameliorated DBL-induced intestinal barrier injury and improved the structural organization of the intestinal flora, restoring the overall composition of the intestinal microbiota., Conclusion: GRR exhibited significant alleviation of DBL-induced liver injury, potentially by modulating FXR/Nrf2-BA-related proteins, reducing hepatic BA accumulation, mitigating liver inflammation and oxidative stress, and regulating intestinal flora., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Gardenia jasminoides J. Ellis (Gardeniae Fructus, GF) is a widely used herbal medicine in many prescriptions. However, inappropriate application of GF may induce hepatotoxicity, which greatly challenges its clinical application. In the field of Traditional Chinese Medicine, the principle of "Compatibility for Toxicity Attenuation" is a pivotal concept. So far, the basis and mechanisms of compatibility with GF remain unclear., Aims of the Study: We aimed to investigate the toxicity attenuating effects and potential mechanisms of compatibility of Coptis chinensis Franch (Coptidis Rhizoma, CR) and GF in hepatotoxicity., Methods and Results: Association rules analysis was performed in 817 GF-related formulas, and 49 associated items were selected, among which CR and GF were ranked in the top two. Network pharmacology was used to elucidate the potential mechanisms of combination of CR and GF in mitigating hepatotoxicity. Nine potential hepatotoxic components of GF and 14 active components of CR were focused on, and 9 common targets for CR and GF were identified. Further GO and KEGG analyses showed that the toxicity attenuating effect of CR on GF-induced hepatotoxicity may be closely correlated with inflammatory response, response to hypoxia, cancer signaling pathways, PI3K-Akt and HIF-1 signaling pathway. The in vitro results indicated that the combined use of CR and GF increased the viability of HepG2 cells. Furthermore, the in vivo data demonstrated that CR inhibited GF-induced increase in serum ALT and AST levels and pathological changes in the livers of KM mice. Besides, CR reduced the accumulation of ROS and MDA, inhibited the release of TNF-α and IL-6, while elevated GSH level in the mouse liver tissues. Finally, the molecular docking results indicated that the active components of CR had strong binding affinity with the monooxygenase cytochrome P450 3A4 (CYP3A4). CR combination restored the expression of CYP3A4 in the liver tissues of mice challenged with GF., Conclusion: Co-administration with CR effectively reduced GF-induced hepatotoxicity through alleviating oxidative damage, inflammatory response and enhancing CYP3A4 expression., Competing Interests: Declaration of competing interest There are no conflicts of interest among the authors participating in this study., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Tamoxifen (TAM) is extensively used to manage estrogen receptor-positive breast cancer. Despite its effectiveness, its administration can negatively impact various organs, including the liver. This research focused on the effects of TAM on the pyroptotic pathway in the liver and evaluated the potential of cardamom extract (CRDE) to lessen hepatic damage of TAM in female rats. Rats received 45 mg/kg of TAM injections for 10 days, while the groups treated with CRDE received 12 ml/kg of CRDE for 20 days, commencing 10 days before TAM administration. TAM exposure resulted in apparent degenerations in hepatic tissue with inflammatory cell infiltration and loss of architectures. Serum levels of liver enzymes including alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase were elevated, along with hepatic oxidative stress, as shown by increased lipid peroxidation with lower levels of reduced glutathione. TAM caused inflammation in the liver tissue as indicated by higher levels of tumor necrosis factor-α and interleukin-6 as well as increased expression of CD68; a phagocytic Kupffer's cells marker. Additionally, the protein expression analysis revealed a high expression of pyroptotic markers including NLRP3-inflammasome, caspase-1, and gasdermin D. Conversely, CRDE treatment effectively neutralized the biochemical, histological, and protein expression alterations induced by TAM. In conclusion, CRDE demonstrated the potential to protect the liver from TAM-induced damage by regulating mechanisms involving oxidative damage, inflammation, and pyroptosis., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Animal ethics: All experimental procedures were reviewed and authorized by the Research Ethics Committee at King Saud University (Ethics Reference No: KSU-SE‐20‐75)., (© 2025. The Author(s).)

Dietary contamination with aflatoxin B 1 (AFB 1 ), which can lead to severe liver damage, poses a great threat to livestock and poultry breeding and has detrimental impacts on food safety. Selenomethionine (SeMet), with anti-inflammatory, antioxidative, and detoxifying effects, is regarded as a beneficial food additive. However, whether SeMet can reduce AFB 1 -induced liver injury and intestinal microbial disorders in rabbits remains to be revealed. Forty 35-day-old rabbits were randomly divided into a control group, an AFB 1 group, and 0.2 mg/kg Se and 0.4 mg/kg Se groups. The SeMet treatment group was fed different doses of the SeMet diet every day for 21 days. On Days 17-21, the AFB 1 group, 0.2 mg/kg Se, and 0.4 mg/kg Se groups were intragastrically administered 0.3 mg AFB 1 /kg b.w. Results showed that SeMet restored alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, alleviating AFB 1 -induced liver function damage. This was linked to changes in intestinal metabolites and activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway. In this study, the relationships between intestinal microorganisms and their metabolites and AFB 1 -induced liver injury are investigated, and the potential protective role of SeMet against liver damage induced by AFB 1 offers novel insights into strategies for the prevention and treatment of AFB 1 -related toxicity.

Immune response gene 1 (IRG1) is highly expressed in mitochondria of macrophages in a pro-inflammatory state. IRG1 and its metabolites play important roles in infection, immune-related diseases and tumor progression by exerting resistance of pathogens, attenuating inflammation and producing antioxidant substances through various pathways and mechanisms. IRG1 deficiency aggravates liver injury. Efferocytosis is a vital mechanism for preventing the progression of inflammatory tissue damage. However, the mechanism by how IRG1/itaconate regulates efferocytosis in autoimmune hepatitis has yet to be fully understood. Therefore, we explored the influence of IRG1-/- on efferocytosis and its effects on regulating the nuclear factor erythroid 2-associated factor 2 (Nrf2)-T-cell immunoglobulin domain and mucin domain 4 (TIM4) pathway and autoimmune liver injury. An autoimmune hepatitis model was established by injecting Con A into wild-type and IRG1-/- mice via the tail vein. Liver injury and inflammatory response were assessed. The efferocytosis role of IRG1-/- macrophages and its potential regulatory mechanisms were also analysed. Exogenous 4-octyl itaconate (OI) supplementation promoted the expression of Nrf2 and TIM4 and restored IRG1-/- bone marrow-derived macrophage (BMDM) efferocytosis, whereas inhibition of Nrf2 mediated by ML385 led to impaired efferocytosis of BMDMs, decreased expression of TIM4, and aggravated liver inflammation injury. Additionally, after supplementing Nrf2-/- BMDMs with exogenous OI, we evaluated the changes in its efferocytosis effect, efferocytosis did not change, and the protective effect of OI disappeared. However, when TIM4 was blocked, the efferocytotic effect of BMDMs was attenuated, inflammatory liver injury and oxidative stress were aggravated. OI promoted the transformation of macrophages into M2 macrophages, and this was inhibited when TIM4 was blocked. To our best understanding, this is the initial exploration to show that TIM4, a downstream molecule of the IRG1/itaconate-Nrf2 pathway, regulates macrophage efferocytosis. These findings suggest a new mechanism and potential treatment for promoting the resolution of inflammation and efferocytosis in autoimmune hepatitis., Competing Interests: Declarations. Ethics approval and consent to participate: The Animal Care and Use Committee of Tongji Medical College of Huazhong University of Science and Technology have approved all animal experiments related to the this study([2023]IACUC Number:3749). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Acetaminophen (N-Acetyl-p-aminophenol: APAP) is one of the most commonly used analgesic/antipyretic drugs with proven safety at therapeutic doses, however, over-dosage causes dose-dependent liver damage, leading to acute liver failure in severe cases. The level of APAP-induced liver injury has been known to vary amongst animal species, and APAP concentrations that induce cell death have been investigated using primary cultured cells. We constructed in vitro model of APAP-induced hepatotoxicity using mouse, rat and human hepatoma cell lines to investigate species differences in the APAP-induced cytotoxicity by monitoring cell death as a marker. The EC50 for each cell line was Hepa1-6 (mouse) < H-4-II-E (rat) < Hep3B (human), whilst the expression of heat shock protein 70 (HSP70), which was a typical molecular chaperone, positively correlated with the EC50 of each cell. Heat shock treatment, which caused activation of heat shock factor 1 (HSF1) followed by significant induction of HSP70, partially suppressed APAP-induced cell death in Hepa1-6 and H-4-II-E. Moreover, HSP70 or HSF1 siRNA treatment in Hep3B enhanced APAP-induced cell death. These results suggest that APAP-induced cell death in hepatoma cell lines may be partly mediated by protein denaturation and that the expression level of HSP70 has an inhibitory effect., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Carbon tetrachloride (CCl 4 ) is a well-known hepatotoxin. This work aimed to assess the therapeutic anti-inflammatory immune potentials of the seaweeds Padina pavonia and Jania rubens extracts on carbon tetrachloride (CCL 4 )-caused liver damage in mice. Our experimentation included two testing regimens: pre-treatment and post-treatment of P. pavonia and J. rubens extracts in CCL 4 /mice. Pre-treatment and post-treatment of P. pavonia and J. rubens extracts in CCL 4 /mice increased WBCs count and lymphocytes relative numbers and reduced the neutrophils and monocytes relative numbers. Pre-treatment and post-treatment of CCL4 /mice with P. pavonia and J. rubens extracts significantly reduced the release amounts of pro-inflammatory cytokines TNF-α and IL-6 and significantly inhibited the increased CRP level. Furthermore, pre-treatment and post-treatment of CCL 4 /mice with P. pavonia and J. rubens extracts recovered the activities of GSH, and significantly decreased MDA level. CCL4/mice pre-treated and post-treated with P. pavonia and J. rubens extracts decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Pre- and post-treatment of CCL 4 /mice with the P. pavonia and J. rubens extracts ameliorated the liver damages caused by CCl 4 and significantly inhibited the necrotic area, indicating hepatic cell death and decreased periportal hepatic degeneration, fibrosis, and inflammation., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval and consent to participate: All animal experimentation protocols were carried out in agreement with the National Institutes of Health guide for the care and use of laboratory animals (NIH Publications No. 8023, revised 1978) and following the recommendation of the proper care and use of laboratory animals regulated by Faculty of Science, Tanta University IACUC, Tanta, Egypt. This study was approved by the Faculty of Science, Tanta University’s Scientific Induction Ethics Committee, and guidelines for the humane care of animals (IACUC-SCI–TU-0412). It is also confirmed that this study is reported in accordance with ARRIVE guidelines. Consent to publish: The authors agreed to publish this manuscript for publication., (© 2025. The Author(s).)

Drug toxicity during the development of candidate pharmaceuticals is the leading cause of discontinuation in preclinical drug discovery and development. Traditionally, the cause of the toxicity is often determined by histological examination, clinical pathology, and the detection of drugs and/or metabolites by liquid chromatography-mass spectrometry (LC-MS). While these techniques individually provide information on the pathological effects of the drug and the detection of metabolites, they cannot provide specific molecular spatial information without additional experiments. Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) is a powerful, label-free technique for the simultaneous detection of pharmaceuticals, metabolites, and endogenous chemical species in tissue sections, which makes it suitable for mechanistic toxicological studies to directly correlate the distribution of the drug and its metabolites with histological findings. This capability was demonstrated by the analysis of the liver from dogs dosed with discontinued drug compound B and its N-desmethyl metabolite, compound A. Histological examination showed multifocal hepatocellular necrosis, bile duct hyperplasia, periportal fibrosis, and chronic inflammation. MALDI-MSI analysis of liver tissue dosed with only compound A indicated that liver lesions were associated exclusively with the parent compound, whereas liver lesions with compound B showed the presence of the parent compound and its two metabolites (compound A and an N-oxide metabolite). Using both positive and negative ion modes, simultaneous detection and identification of endogenous molecular markers of the connective tissue, blood vessels, liver parenchyma, and bile duct epithelium was achieved, allowing optimal visualization of histological lesions by mass spectrometry imaging.

Drug-induced liver injury (DILI) has emerged as an urgent clinical challenge. It is characterized by mitochondrial dysfunction in liver cells, which leads to abnormal changes in H 2 O 2 levels within the mitochondria. Super-resolution imaging allows for the observation of the fine structure of mitochondria at the nanometer scale, potentially enabling the detection of mitochondrial H 2 O 2 levels during DILI at the subcellular organelle level. Here, we report the design and synthesis of a novel H 2 O 2 -activated probe for the detection of mitochondrial H 2 O 2 levels. SML is a near-infrared (NIR) fluorescent probe with a large Stokes shift (260 nm) and a sensing mechanism based on intramolecular charge transfer (ICT) switching. Super-resolution imaging of mitochondrial H 2 O 2 was conducted using structured illumination microscopy (SIM). The improved accuracy in observing periods of mitochondrial dysfunction allows the SML probe to be effectively utilized for the rapid monitoring nanoscale upregulation of H 2 O 2 during DILI and hepatic fibrosis, thus providing SML with the capability to screen for effective therapeutic candidates.

Background: Geniposide, a prominent iridoid glycoside derived from Gardenia jasminoides J . Ellis, has garnered attention due to its association with hepatotoxicity despite its well-documented pharmacological efficacy in preclinical and clinical contexts. The NOD-like receptor protein 3 (NLRP3) inflammasome is implicated in numerous pathological conditions, including drug-induced liver injury. This study aims to explore the involvement of the NLRP3 inflammasome in geniposide-induced liver toxicity. Methods: Rats were administered geniposide for 5 days, concurrently treated with or without glibenclamide (GLY), an in vivo inhibitor of NLRP3. In vitro, HL-7702 cells were exposed to genipin (a metabolite of geniposide via hepatointestinal circulation), with or without GLY supplement. Liver tissue was examined through pathological sections. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GT), and total bilirubin (T-Bil) levels were determined using the enzyme plate method. IL-1 β and IL-18 levels in the supernatant and serum were quantified through ELISA. Apoptosis-associated speck-like protein (ASC), NLRP3, caspase-1, pro-IL-1 β , and pro-IL-18 mRNA levels in cells or the liver were assessed by RT-PCR. Protein levels of ASC, NLRP3, caspase-1, pro-IL-1 β , and pro-IL-18 in cells or the liver were analyzed by Western blot. Results: Rats treated with geniposide displayed notable liver damage characterized by inflammatory infiltration, elevated serum transaminases, and heightened levels of inflammatory factors IL-1 β and IL-18. This liver damage was concomitant with NLRP3 inflammasome activation within the liver. Furthermore, genipin induction led to reduced cell viability, increased transaminases in the cell supernatant, and an upsurge in inflammatory factors, resulting in heightened NLRP3 inflammasome expression within the cells. However, GLY effectively curtailed excessive NLRP3 activation, dampened the production of inflammatory factors IL-1 β and IL-18, and ameliorated liver damage caused by geniposide. Conclusions: Our findings collectively elucidate that geniposide induces hepatotoxicity by triggering NLRP3 inflammasome signaling. Inhibition of the inflammasome presents a promising novel therapeutic target for mitigating geniposide-induced hepatotoxicity., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2025 Yixuan Liu et al. Mediators of Inflammation published by John Wiley & Sons Ltd.)

Ferroptosis is a form of regulated cell death closely associated with glutathione depletion and accumulation of reactive lipid peroxides. In this study, we seek to determine whether 2-hydroxyestrone (2-OH-E 1 ) and 2-hydroxyestradiol (2-OH-E 2 ), 2 major metabolites of endogenous estrone (E 1 ) and 17β-estradiol (E 2 ) formed by cytochrome P450 in the liver, can protect against erastin- and RSL3-induced ferroptosis in hepatoma cells (H-4-II-E and HuH-7) in vitro and acetaminophen-induced mouse liver injury in vivo. We find that 2-OH-E 1 and 2-OH-E 2 can protect, in a dose-dependent manner, H-4-II-E hepatoma cells against erastin/RSL3-induced ferroptosis. A similar protective effect of 2-OH-E 1 and 2-OH-E 2 against erastin- and RSL3-induced ferroptosis is also observed in HuH-7 hepatoma cells. These 2 estrogen metabolites can strongly abrogate erastin- and RSL3-induced accumulation of cellular NO, reactive oxygen species (ROS), and lipid-ROS. Mechanistically, 2-OH-E 1 and 2-OH-E 2 protect cells against chemically induced ferroptosis by binding to cellular protein disulfide isomerase and then inhibiting its catalytic activity and reducing protein disulfide isomerase-mediated activation (dimerization) of inducible nitric oxide synthase, abrogating cellular NO, ROS, and lipid-ROS accumulation. Animal studies show that 2-OH-E 1 and 2-OH-E 2 also exhibit strong protection against acetaminophen-induced liver injury in mice. Interestingly, although E 1 and E 2 have a very weak protective effect in cultured hepatoma cells, they exhibit a similarly strong protective effect as 2-OH-E 1 and 2-OH-E 2 in vivo, suggesting that the metabolic conversion of E 1 and E 2 to 2-OH-E 1 and 2-OH-E 2 contributes importantly to their hepatoprotective effect. This study reveals that 2-OH-E 1 and 2-OH-E 2 are important endogenous factors for protection against chemically induced liver injury in vivo. SIGNIFICANCE STATEMENT: Ferroptosis is an iron-dependent and lipid reactive oxygen species-dependent form of regulated cell death. Recent evidence has shown that protein disulfide isomerase (PDI) is an important mediator of chemically induced ferroptosis and also a new target for ferroptosis protection. This study shows that 2-hydroxyestrone and 2-hydroxyestradiol are 2 inhibitors of PDI that can strongly protect against chemically induced ferroptotic hepatocyte death in vitro and in vivo. This work supports a PDI-mediated, estrogen receptor-independent mechanism of hepatocyte protection by 2-hydroxyestrone and 2-hydroxyestradiol., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Highly active antiretroviral therapy (HAART), consisting of three or more antiretroviral drugs, is recommended for patients with HIV infection. HAART effectively reduces HIV RNA levels, lowers the risk of opportunistic infections, and improves immune function and survival rates. However, it is also associated with an increased risk of liver injury in HIV-infected individuals. This review aims to summarize the mechanisms underlying HAART-induced liver injury. A comprehensive search was conducted in PubMed and EMBASE using keywords such as "Antiretroviral/ARV drugs and drug-induced liver injury (DILI)," "HAART and DILI," "Antiretroviral therapy and DILI," and "HIV infection and DILI." Relevant papers published before March 2024 were included. Experimental studies have demonstrated that zidovudine and efavirenz can cause structural alterations in mitochondria, impair the respiratory chain, generate free radicals, and deplete mitochondrial DNA, leading to oxidative and endoplasmic reticulum stress, as well as the accumulation of advanced glycation end products in liver tissue. Zidovudine disrupts lipid homeostasis by increasing fatty acid synthesis and reducing metabolism. Efavirenz and its metabolite, 8-hydroxyefavirenz, induce hepatocellular death and activate proapoptotic markers through c-Jun N-terminal kinase signaling. Additionally, lamivudine has been shown to induce liver injury and oxidative stress in rats. Clinically, approximately 50% of HIV patients on HAART regimens containing non-nucleoside reverse transcriptase inhibitors experience mild to moderate liver injury. HAART regimens that include efavirenz, lamivudine, and tenofovir impair glucose and lipid homeostasis in rats, highlighting the need for caution in HIV patients with fatty liver disease. Patients with viral hepatitis coinfection, those taking antitubercular drugs or cotrimoxazole, and those on nevirapine-containing regimens are at particularly high risk. Regular monitoring of liver function is essential to prevent liver damage associated with HAART in HIV-infected patients. While HAART significantly improves survival rates in HIV patients, it also poses a considerable risk of liver injury, necessitating careful monitoring and management., (© 2025 Wiley Periodicals LLC.)

Cyclophosphamide (CYC) is one of the most potent antineoplastic drugs; however, hepatonephrotoxicity, observed following its use, remains one of its most severe side effects. Previous studies have reported that syringaldehyde (SYA), a flavonoid compound, exhibits anti-inflammatory and antioxidant properties. However, it is unclear whether SYA has any effects on hepatonephrotoxicity caused by the side effects of antineoplastic drugs. In the present research, we thoroughly evaluated the effects of SYA on cyclophosphamide-induced hepatonephrotoxicity in a mouse model, focusing on Nrf2/HO-1 pathway activation. In the present study, SYA (25 and 50 mg/kg, p.o.) and CYC (30 mg/kg, i.p.) were delivered to male mice for 10 days to induce hepatonephrotoxicity. SYA treatment alleviated the elevated levels of AST, ALT, BUN, and creatinine caused by CYC. It further suppressed lipid peroxidation by lowering MDA levels and enhanced antioxidant defense by elevating GSH, SOD, and CAT levels. Additionally, SYA increased the mRNA expression levels of HO-1, Nrf2, and Bcl-2, which had been reduced due to oxidative stress, inflammatory, and apoptotic pathways, while suppressing the elevated gene expression levels of NFκB, TNF-α, Bax, and Cas-3. Furthermore, SYA regulated the altered protein expression levels of Nrf2, Cas-3, Bax, and Bcl-2 induced by CYC. Microscopically, SYA also mitigated liver and kidney tissue damage caused by CYC. In conclusion, SYA significantly reduced CYC-induced hepatonephrotoxicity by inhibiting inflammation, oxidative stress, and apoptosis by employing the Nrf2/NFκB/HO-1 pathway. These findings indicate that SYA has the possibility as a treatment option agent in the case of prevention of liver and kidney damage., (© 2025 Wiley Periodicals LLC.)

Acute hepatic injury (AHI) is associated with poor prognosis in sepsis patient; however, to date, no specific therapeutic approach has been established for this disease. Therefore, we aimed to explore the effects and action mechanisms of Astragaloside IV (AS) on AHI. C57BL/6 mice, RAW264.7 cells, and bone marrow-derived macrophages were used in this study. Sepsis-associated AHI model mice were established using lipopolysaccharide + D-galactosamine. Pathological examination of liver tissues and serum alanine aminotransferase/aspartate aminotransferase was performed to evaluate the liver function. Moreover, inflammatory cytokine levels, proportion of M1/M2 macrophages and their marker levels, and cell pyroptosis-related indicator levels were determined in the liver of the AHI model mice with or without AS treatment. AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) expression was determined after AS treatment. Additionally, inflammatory cytokine levels, liver injury, and macrophage polarization were evaluated after inhibiting the AMPK/SIRT1 pathway. AS alleviated lipopolysaccharide + D-galactosamine-induced AHI and inhibited inflammatory reactions in the blood and liver of mice. AS also promoted the M1-to-M2 phenotypic transformation of macrophages in the liver of AHI model mice and in vitro, thereby decreasing the pro-inflammatory cytokine levels and increasing the anti-inflammatory cytokine levels. AS increased AMPK and SIRT1 levels in the liver and macrophages. Furthermore, AS improved liver injury by elevating the expression of the AMPK/SIRT1 signaling pathway and inhibiting pyroptosis in macrophages. Overall, AS alleviated AHI by promoting M1-to-M2 macrophage transformation and inhibiting macrophage pyroptosis via activation of the AMPK/SIRT1 signaling pathway., (© 2024 John Wiley & Sons, Ltd.)

Background: Mirabegron (MIRG) is a type of β3 adrenoceptor agonist that is considered an alternative therapy for the treatment of overactive bladder (OAB) symptoms. Cilostazol (CITZ) is a selective inhibitor of phosphodiesterase (III) that has various pharmacological effects., Objectve: The current study aimed to highlight the regulatory effects of CITZ on MIRG-induced toxicity., Materials and Methods: Male rats were divided into six groups. Blood samples were collected to determine different hepatic and kidney function levels along with serum protein electrophoresis and inflammatory factor levels. Histopathological studies and oxidative stress (OS) were also assessed. Kidney and hepatic damage were detected following the administration of MIRG, especially at high doses, due to elevated OS, inflammation, and apoptotic marker levels., Results: Rats receiving CITZ exhibited significant improvements in both hepatic and kidney functions, with decreased inflammation and OS., Conclusion: CITZ administration plays a beneficial role in alleviating hepatic and nephrotoxicity induced by MIRG by inhibiting OS and inflammation.

The present study evaluated the hepato-nephronal protective properties of Crataegus azarolus berries decoction extract (CAB-DE) on acetic acid (AA)-induced oxidative stress and metabolic disorders in rats. Animals (60 rats) were randomly divided into six groups (n = 10), with groups 1 and 2 being controls and groups 3, 4, and 5 given increasing doses of CAB-DE, group 6 were given gallic acid until ulcerative colitis was induced and then intoxicated by an acute intra-rectal infusion of AA. Our results showed that CAB-DE-oral administration had no signs of toxicity or abnormal behavior in rats, with a LD 50 higher than 3500 mg/kg bw. In addition, CAB-DE protected against AA-induced nephropathy and hepatic damage in rats, as determined by an increase in organ weights and an alteration in the renal and liver parameters and functions. Moreover, extract co-administration reduced AA-induced liver and kidney lipoperoxidation, maintained non-enzymatic contents such as sulfhydryl groups (-SH) and reduced glutathione (GSH), and restored antioxidant enzyme activities, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Finally, CAB-DE might have a possible protective effect against AA-oxidative stress and dysfunction in the rat liver and kidney, suggesting that Crataegus azarolus berries may be beneficial for people suffering from liver issues and nephropathy., (© 2025 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Cisplatin (CP) is an antineoplastic drug associated with various cytotoxic adverse effects, including hepatotoxicity. Exercise training may offer hepatoprotection by improving redox status. This study compared the effects of light-intensity continuous training (LICT), moderate-intensity continuous training (MICT), and high-intensity interval training (HIIT) on CP-induced hepatotoxicity in female Wistar rats. The rats were divided into five groups (n = 7): sedentary control (C + S), CP and sedentary (CP + S), CP with LICT (CP + LICT), CP with MICT (CP + MICT), and CP with HIIT (CP + HIIT). The training protocols involved eight weeks of treadmill exercise before CP administration (5 mg/kg). Seven days after CP injection, the rats were euthanized to collect blood and liver tissue samples. Our findings demonstrate that HIIT was the most effective protocol in preventing histopathological alterations and reducing oxidative and nitrosative damage markers in macromolecules, including 4-HNE (lipids), nitrotyrosine (proteins), and 8-OHdG (DNA). The reduction in these markers appears to be linked to decreased CYP2E1 levels. Moreover, HIIT activated the Nrf2 pathway and upregulated its downstream antioxidant enzymes, including SOD1, catalase, GPx, and HO-1. In conclusion, HIIT emerged as the most effective protocol for mitigating hepatic damage, likely through CYP2E1 suppression and enhancement of antioxidant defenses via Nrf2 signaling pathway activation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

This study aims to evaluate the hepatoprotective effect of alpha-pinene against N-acetyl-p-aminophenol, paracetamol, (APA)-induced liver damage in rats. Thirty Wistar rats were divided into five groups (n = 6): Group 1: Normal (control). Group 2: APA 640 mg/kg. Group 3: alpha-pinene 50 mg/kg (APA+ αPi 50 mg/kg). Group 4: alpha-pinene 100 mg/kg (APA+ αPi 100 mg/kg). Group 5: silymarin 50 mg/kg (APA+ SIL). Alpha-pinene or silymarin was orally administered after APA administration for 14 consecutive days. This study investigated liver damage by preparing pathology slides from liver tissue. Levels of AST, ALT, ALP, total bilirubin, total antioxidant capacity (TAC), and total oxidant status (TOS) were measured. Inflammatory factors, including NF-kB gene expression and levels of IL-6 and TNF-a, were also measured. Administering alpha-pinene with APA can prevent liver damage induced by APA. Alpha-pinene can enhance TAC while reducing TOS, ALT, AST, ALP, and total bilirubin. Moreover, the results have also revealed that alpha-pinene decreases NF-kB expression, which leads to a reduction in IL-6 and TNF-a levels. It appears that alpha-pinene induces liver protective effects against APA damage by reducing the activity of liver enzymes, improving antioxidant/oxidative status, and reducing inflammation through the regulation of NF-kB and pro-inflammatory cytokines., (© 2025 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Isoniazid and rifampicin co-therapy are the main causes of anti-tuberculosis drug-induced liver injury (ATB-DILI) and acute liver failure, seriously threatening human health. However, its pathophysiology is not fully elucidated. Growing evidences have shown that fibroblast growth factors (FGFs) play a critical role in diverse aspects of liver pathophysiology. The aim of this study is to investigate the role of FGFs in the pathogenesis of isoniazid (INH) and rifampicin (RIF)-induced liver injury. Through systematic screening, this study finds that hepatic FGF1 expression is significantly downregulated in both mouse model and human patients challenged with INH and RIF. Hepatocyte-specific Fgf1 deficiency exacerbates INH and RIF-induced liver injury resulted from elevated bile acids (BAs) synthases and aberrant BAs accumulation. Conversely, pharmacological administration of the non-mitogenic FGF1 analog - FGF1 ΔHBS significantly alleviated INH and RIF-induced liver injury via restoring BAs homeostasis. Mechanically, FGF1 repressed hepatocyte nuclear factor 4α (Hnf4α) transcription via activating FGF receptor 4 (FGFR4)-ERK1/2 signaling pathway, thus reducing BAs synthase. The findings demonstrate hepatic FGF1 functions as a negative regulator of BAs biosynthesis to protect against INH and RIF-induced liver injury via normalizing hepatic BAs homeostasis, providing novel mechanistic insights into the pathogenesis of ATB-DILI and potential therapeutic strategies for treatment of ATB-DILI., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Approximately 20 million new cancer cases have occurred worldwide, and dose limitation occurs because of the liver and kidney toxicity of chemotherapeutic agents. Inflammation/apoptosis/ROS pathways appear to be activated in the liver and kidney toxicity of chemotherapeutic agents. This study was conducted to investigate the potential effects of silymarin (SLY) use against docetaxel (DTX)-induced liver and kidney damage in rats. For this purpose, 30 mg/kg DTX was administered intraperitoneally to Sprague Dawley rats on the first day of the study, followed by SLY (25 or 50 mg/kg/day) orally for 7 days. Then, various analyses were performed on liver and kidney tissues using biochemical, molecular and histological methods. The data obtained showed that DTX administration suppressed antioxidant markers and increased lipid peroxidation in liver and kidney tissues. It was also determined that DTX administration triggered markers of endoplasmic reticulum stress, inflammation, apoptosis and autophagy. On the other hand, SLY treatment increased enzymatic and non-enzymatic antioxidant levels and decreased malondialdehyde levels. Additionally, SLY alleviated DTX-induced endoplasmic reticulum stress, inflammation, apoptosis and autophagy in liver and kidney tissues. Immunohistochemical analyses showed that DTX increased the density of 8-OHdG positive cells in liver and kidney tissues, while oxidative DNA damage decreased after SLY administration. ALT, AST, ALP, Urea and Creatinine levels increased in the DTX group and decreased in the SLY treatment groups. In conclusion, DTX administration caused toxicity in liver and kidney tissues and damaged tissue integrity, while SLY treatment alleviated DTX-induced toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aflatoxin B1 (AFB1) has been reported to synergize with hepatitis B virus (HBV) to induce development of hepatocellular carcinoma (HCC). Precise daily exposure to AFB1 and its contribution to liver injury have not been quantified and have even been disregarded due to lack of convenient detection, and the strong species specificity of HBV infection has restricted research on their synergistic harm. Hence, our objective was to investigate the molecular mechanisms by which AFB1 exacerbates HBV-related injury. We constructed tree shrew models with 400 μg HBV plasmid and 4 mg/kg AFB1 co-exposure for 4-6 days. Injury and molecule expression resulting from HBV and AFB1 toxicity were observed in vivo and in vitro. Expression datasets of tree shrew livers, human HCC, and pregnane X receptor (PXR) activation were employed to screen vital pathways and target genes. The oncogenic hepatitis B virus x (HBx) protein, HBV-related histopathological damage, metabolic dysregulation, and several cancer-related signaling pathways were enriched in injured tree shrew livers, and PXR signaling was inhibited after co-exposure to HBV and AFB1. Furthermore, in human HCC and HBV-integrated Hep3B and HepG2.215 cells, FTCD Antisense RNA 1 (FTCD-AS1), PXR and mannose-binding lectin-associated serine protease 1 (MASP1) exhibited strong correlation. Overexpression of FTCD-AS1 and PXR alleviated cell damage in exposure to 5 μM AFB1 for 48 h. In summary, inactivation of the FTCD-AS1-PXR-MASP1 axis was pinpointed as the key event in AFB1-enhanced HBV infection, metabolic dysregulation and carcinogenic injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Acetaminophen (APAP) overdose stands as the paramount contributor to drug-elicited liver damage in clinical settings. Despite this, the intricate interplay between uric acid (UA) levels, its metabolism-linked regulatory genes, and their effects on APAP metabolism and hepatic functions remains elusive. Our study sheds light on this nexus, uncovering that uric acid concentrations and urate transporter-1 (URAT1) expression are intricately intertwined in APAP-induced hepatotoxicity. Notably, elevated serum uric acid levels concomitant with a marked downregulation of hepatic URAT1 expression were discernible in APAP-mediated liver injury models. We also found that high UA exacerbated APAP-induced liver injury in vitro and in vivo. To delve deeper, we devised genetic knockout mice models, specifically targeting URAT1, to unravel its pivotal role in this pathological process. Strikingly, Urat1 knockout (Urat1 -/- ) mice exhibited exacerbated APAP-triggered hepatotoxicity when juxtaposed against their genetically intact wild-type (Urat1 +/+ ) counterparts, accompanied by increased serum and hepatic UA contents. However, the changes in UA levels might not be the only factor exacerbating APAP liver injury in Urat1 -/- mice, as Urat1 knockout has also been proved to affect many other metabolites associated with the redox homeostasis. Mechanistically, we found that the ablation of Urat1 not only intensified triglyceride accumulation instigated by APAP via inhibiting PPAR-α pathway but also ignited the NLRP3/NF-κB and JNK/ERK signaling cascades, and disrupted oxidative stress homeostasis via downregulating KEAP1/NRF2 pathway. Collectively, our findings underscore that URAT1 acts as a multifaceted facilitator of APAP-induced liver injury in mice, thereby positioning it as a genetic vulnerability factor in APAP overdose scenarios., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Acetaminophen (APAP) is a widely used analgesic and antipyretic medicine. It is frequently employed to alleviate pain and mitigate fever-related symptoms, but it can cause liver injury or even liver failure when overdosed. Isorhapontigenin, a compound derived from Chinese herbs and grapes, has been demonstrated to exhibit antioxidant and anti-inflammatory effects. This study focused on evaluating the effect of isorhapontigenin in alleviating APAP-induced liver injury. In the study, a single intraperitoneal administration of APAP was employed to induce liver injury, and isorhapontigenin was given orally 3 days before or 1 h after APAP administration. The results revealed that isorhapontigenin significantly mitigated liver injury by effectively inhibiting APAP-induced apoptosis, oxidative stress, and inflammation. Furthermore, transcriptomic RNA sequencing of liver tissues indicated that isorhapontigenin probably protected against APAP-induced liver injury by promoting fatty acid oxidation. Pharmacological experiments also demonstrated that isorhapontigenin treatment led to a significant reduction in triglyceride accumulation, increased ATP levels and direct fatty acid oxidation activity, as well as enhanced expression of proteins associated with fatty acid oxidation, including PPAR-α, PGC-1α, and CPT-1A. Moreover, the protective effects of isorhapontigenin against APAP-induced liver injury were abolished by a CPT-1A inhibitor, etomoxir. Notably, we found that combining isorhapontigenin with NAC (N-acetyl-L-cysteine) resulted in a more significant alleviation of APAP-induced liver injury compared to NAC alone. In conclusion, our study indicates that isorhapontigenin is a potential therapeutic strategy that works by regulating fatty acid oxidation to alleviate APAP-induced liver injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Trichloroethylene (TCE) is a volatile, colorless liquid that is widely used as a chlorinated organic vehicle in industrial production and processing industries. Many workers exposed to trichloroethylene may develop trichloroethylene hypersensitivity syndrome (THS). However, the underlying mechanism of THS is still unclear, especially liver injury. The present study aimed to investigate whether Wnt5a/c-Jun N-terminal kinase (JNK) is involved in and regulates liver injury caused by TCE exposure and to provide new directions for the prevention and treatment in clinical settings of liver injury caused by TCE exposure. We used 6- to 8-week-old SPF-grade BALB/c female mice to establish a TCE sensitization model and explored the mechanism through inhibitor intervention. We found that the expression of Wnt5a/JNK was significantly elevated in the liver of TCE sensitization-positive mice. Inhibitors of Wnt Production 2 (IWP-2) are known antagonists of the Wnt pathway. TCE-sensitization mice treated with IWP-2 showed downregulated Wnt5a/JNK expression, reduced Kupffer cell activation, and decreased liver injury. At the same time, we found that phosphorylated JNK in TCE-sensitization mouse livers and extracted Kupffer cells showed a significant downward trend after inhibition of Wnt5a function. We also found that a specific JNK inhibitor, SP600125, decreased the secretion of cytokines and chemokines and decreased Kupffer cell activation. We demonstrated that Wnt5a/JNK was involved in the regulation of liver injury in TCE-sensitization mice and that it exacerbated liver injury by activating Kupffer cells and releasing chemokines. We therefore hypothesized that Kupffer cell activation was affected by JNK, which reduced chemokine and cytokine secretion and attenuated liver injury in TCE-sensitization mice., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.