Search

Peroxiredoxin 6 (Prdx6) repairs peroxidized membranes by reducing oxidized phospholipids, and by replacing oxidized sn-2 fatty acyl groups through hydrolysis/reacylation by its phospholipase A2 (aiPLA2) and lysophosphatidylcholine acyltransferase activities. Prdx6 is highly expressed in the lung, and intact lungs and cells null for Prdx6 or with single-point mutations that inactivate either Prdx6-peroxidase or aiPLA2 activity alone exhibit decreased viability, increased lipid peroxidation, and incomplete repair when exposed to paraquat, hyperoxia, or organic peroxides. Ferroptosis is form of cell death driven by the accumulation of phospholipid hydroperoxides. We studied the role of Prdx6 as a ferroptosis suppressor in the lung. We first compared the expression Prdx6 and glutathione peroxidase 4 (GPx4) and visualized Prdx6 and GPx4 within the lung. Lung Prdx6 mRNA levels were five times higher than GPx4 levels. Both Prdx6 and GPx4 localized to epithelial and endothelial cells. Prdx6 knockout or knockdown sensitized lung endothelial cells to erastin-induced ferroptosis. Cells with genetic inactivation of either aiPLA2 or Prdx6-peroxidase were more sensitive to ferroptosis than WT cells, but less sensitive than KO cells. We then conducted RNA-seq analyses in Prdx6-depleted cells to further explore how the loss of Prdx6 sensitizes lung endothelial cells to ferroptosis. Prdx6 KD upregulated transcriptional signatures associated with selenoamino acid metabolism and mitochondrial function. Accordingly, Prdx6 deficiency blunted mitochondrial function and increased GPx4 abundance whereas GPx4 KD had the opposite effect on Prdx6. Moreover, we detected Prdx6 and GPx4 interactions in intact cells, suggesting that both enzymes cooperate to suppress lipid peroxidation. Notably, Prdx6-depleted cells remained sensitive to erastin-induced ferroptosis despite the compensatory increase in GPx4. These results show that Prdx6 suppresses ferroptosis in lung endothelial cells and that both aiPLA2 and Prdx6-peroxidase contribute to this effect. These results also show that Prdx6 supports mitochondrial function and modulates several coordinated cytoprotective pathways in the pulmonary endothelium.

Osteosarcoma (OS) is the most common malignant bone tumor with a poor prognosis. Here, we show that the nuclear receptor RORγ may serve as a potential therapeutic target in OS. OS exhibits a hyperactivated oxidative phosphorylation (OXPHOS) program, which fuels the carbon source to promote tumor progression. We found that RORγ is overexpressed in OS tumors and is linked to hyperactivated OXPHOS. RORγ induces the expression of PGC-1β and physically interacts with it to activate the OXPHOS program by upregulating the expression of respiratory chain component genes. Inhibition of RORγ strongly inhibits OXPHOS activation, downregulates mitochondrial functions, and increases ROS production, which results in OS cell apoptosis and ferroptosis. RORγ inverse agonists strongly suppressed OS tumor growth and progression and sensitized OS tumors to chemotherapy. Taken together, our results indicate that RORγ is a critical regulator of the OXPHOS program in OS and provides an effective therapeutic strategy for this deadly disease.

Although cold preservation remains the gold standard in organ transplantation, cold stress-induced cellular injury is a significant problem in clinical orthotopic liver transplantation (OLT). Because a recent study showed that cold stress activates ferroptosis, a form of regulated cell death, we investigated whether and how ferroptosis determines OLT outcomes in mice and humans. Treatment with ferroptosis inhibitor (ferrostatin-1) during cold preservation reduced lipid peroxidation (malondialdehyde; MDA), primarily in liver sinusoidal endothelial cells (LSECs), and alleviated ischemia/reperfusion injury in mouse OLT. Similarly, ferrostatin-1 reduced cell death in cold-stressed LSEC cultures. LSECs deficient in nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of ferroptosis, were susceptible to cold stress-induced cell death, concomitant with enhanced endoplasmic reticulum (ER) stress and expression of mitochondrial Ca2+ uptake regulator (MICU1). Indeed, supplementing MICU1 inhibitor reduced ER stress, MDA expression, and cell death in NRF2-deficient but not WT LSECs, suggesting NRF2 is a critical regulator of MICU1-mediated ferroptosis. Consistent with murine data, enhanced liver NRF2 expression reduced MDA levels, hepatocellular damage, and incidence of early allograft dysfunction in human OLT recipients. This translational study provides a clinically applicable strategy in which inhibition of ferroptosis during liver cold preservation mitigates OLT injury by protecting LSECs from peritransplant stress via an NRF2-regulatory mechanism.

BACKGROUND: Ferroptosis is strongly associated with the occurrence and progression of osteoarthritis, but the specific characteristic genes and regulatory mechanisms are not known. OBJECTIVE: To identify osteoarthritis ferroptosis signature genes and immune infiltration analysis using the WGCNA and various machine learning methods. METHODS: The osteoarthritis dataset was downloaded from the GEO database and ferroptosis-related genes were obtained from the FerrDb website. R language was used to batch correct the osteoarthritis dataset, extract osteoarthritis ferroptosis genes and perform differential analysis, analyze differentially expressed genes for GO function and KEGG signaling pathway. WGCNA analysis and machine learning (random forest, LASSO regression, and SVM-RFE analysis) were also used to screen osteoarthritis ferroptosis signature genes. The in vitro cell experiments were performed to divide chondrocytes into normal and osteoarthritis model groups. The dataset and qPCR were used to verify expression and correlate immune infiltration analysis. RESULTS AND CONCLUSION: (1) 12 548 osteoarthritis genes were obtained by batch correction and PCA analysis, while 484 ferroptosis genes were obtained, resulting in 24 differentially expressed genes of osteoarthritis ferroptosis. (2) GO analysis mainly involved biological processes such as response to oxidative stress and response to organophosphorus, cellular components such as apical and apical plasma membranes, and molecular functions such as heme binding and tetrapyrrole binding. (3) KEGG analysis exhibited that differentially expressed genes of osteoarthritis ferroptosis were related to signaling pathways such as the interleukin 17 signaling pathway and tumor necrosis factor signaling pathway. (4) After using WGCNA analysis and machine learning screening, we obtained the characteristic gene KLF2. After validation by gene microarray, we found that the gene expression of KLF2 was higher in the test group than in the control group in the meniscus (P=0.000 14). (5) In vitro chondrocyte assay showed that type II collagen and KLF2 expression was lower in the osteoarthritis group than in the control group in chondrocytes (P < 0.05), while in osteoarthritis ferroptosis, mast cells activated was closely correlated with dendritic cells (r=0.99); KLF2 was closely correlated with natural killer cells (r=-1, P=0.017) and T cells follicular helper (r=-1, P=0.017). (6) The findings indicate that using WGCNA analysis and machine learning methods confirmed that KLF2 can be a characteristic gene for osteoarthritis ferroptosis and may improve osteoarthritis ferroptosis by interfering with KLF2. [ABSTRACT FROM AUTHOR]

Communication between subcellular organelles is crucial for a synchronized cellular response which drives the search for chemical tools to simultaneously visualize dual organelles to unveil these dynamic interactions. A polarity‐sensitive dual organelle targeting dioxaborine derivative, namely DOBEL, which stains lipid droplets (LDs) and endoplasmic reticulum (ER) simultaneously is introduced. This report is the first to demonstrate how the intrinsic difference in micropolarity drives the visualization of LDs in the green channel while ER in the red channel involves a single probe. The in situ emission spectra inside these organelles allow polarity quantification, further leading to deciphering the unique microenvironments in different cell lines. Exploiting ratiometric fluorescence imaging revealed how the micropolarity inside both LDs and ER alters during Ferroptosis. Altogether, DOBEL can be used as a superior imaging tool for monitoring LD‐ER interaction during regular status and ferroptosis‐related diseases in living cells. [ABSTRACT FROM AUTHOR]

Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment. Synopsis: The interdependence of oncogenic drivers, cell proliferation and energy metabolism in glioma resistance remains unclear. This study uncovers a unique, targetable metabolic vulnerability of quiescent astrocyte-like glioma cells otherwise resistant to standard forms of treatment. Activating Notch at early stages of gliomagenesis in a retrovirus-induced mouse model drives tumors with an astrocyte-like phenotype. Astrocyte-like glioma cells show decreased mitochondrial respiration and altered complex I function, but increased lipid peroxidation and ROS production. Astrocyte-like glioma cells are specifically vulnerable to the inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treating acute slices generated from human glioma surgical samples with GPX4 inhibitors selectively depletes the quiescent astrocyte-like tumor cells. Quiescent astrocyte-like glioma cells show abnormal energy metabolism, which renders them sensitive to ferroptosis-inducing drugs. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion (I/R) is an important inducer of acute kidney injury (AKI), and triggers the generation of reactive oxygen species (ROS) and the expression of matrix metalloproteinase 2 (MMP2), exacerbating kidney damage. Given the immense potential of vitamin E (VitE) as a natural fat-soluble antioxidant in kidney protection, we designed the nanoparticles (NPs) that could dual respond to ROS and MMP2, aiming to accurately deliver VitE to renal injury cells. The NPs utilized Gel-SH as a sensitive receptor for MMP2 and diselenide as a sensitive receptor for ROS, while PEG2k modification enhanced biocompatibility and prevented phagocytosis mediated by the mononuclear phagocyte system. The amphiphilic Gel-SH and diselenide encapsulate the liposoluble VitE and self-assemble into the NPs with a hydrodynamic size of 69.92 nm. Both in vivo and in vitro experiments based on these NPs show good biocompatibility and the ability of target renal injury cells. In vivo kidney I/R injury models and in vitro cell hypoxia/reoxygenation models, the NPs have demonstrated effects in reducing oxidative stress and alleviating AKI. Notably, VitE can preferentially react with peroxyl radical (LOO•) than polyunsaturated fatty acid (PUFA), inhibiting the formation of carbon centered radical (L•), thereby blocking the chain reaction between PUFA and LOO• in ferroptosis. The NPs also inhibit the transition from AKI to chronic kidney disease, with few side effects. Thus, the NPs with dual-responsiveness to MMP2 and ROS for targeted delivery of VitE to renal injury cells exhibit remarkable effects in inhibiting ROS and the chain reactions of ferroptosis, making it a promising therapeutic agent against AKI caused by I/R. [ABSTRACT FROM AUTHOR]

Altering the mechanisms of tumor cell death and overcoming the limitations of traditional chemotherapy is pivotal to contemporary tumor treatment. Inducing ferroptosis, while circumventing safety concerns associated with ferrous vectors, through nonferrous ferroptosis is a promising but underexplored frontier in cancer therapy. Histidine phosphatase (LHPP) has emerged as a novel therapeutic target in treating hepatocellular carcinoma (HCC), but the precise mechanism of LHPP against HCC remains unclear. Herein, we explore the effects of upregulating LHPP expression on ferroptosis and tumor immunogenicity induction by simply delivering a miRNA-363-5p inhibitor (miR-363-5pi) via a previously optimized gemcitabine-oleic acid (GOA) prodrug. Efficient miRNA encapsulation was achieved through hydrogen bonding at an optimized GOA/miRNA molar feed ratio of 250:1, affording spherical nanoparticles with a uniform hydrodynamic size of 147.1 nm and a negative potential of -21.5 mV. The mechanism of this LHPP-ferroptosis crosstalk is disclosed to be an inhibited phosphorylation of the PI3K/Akt pathway, leading to a remarkable tumor inhibition rate of 88.2% in nude mice bearing Bel-7402 tumor xenografts via a combination of LHPP-triggered nonferrous ferroptosis and GOA-induced chemotherapy. The biocompatibility of GOA/miR-363-5pi is strongly supported by their non-hematologic toxicity and insignificant organ damage. In addition, the tumor immunogenic activation potential of GOA/miR-363-5pi was finally explored. Overall, this study is the first work that elucidates the precise mechanism of LHPP for treating HCC via ferroptosis induction and achieves the transformation of chemotherapy and gene therapy into ferroptosis activation with tumor cell immunogenicity, which lays a new therapeutic foundation for the clinical treatment of HCC. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC), a highly aggressive form of breast cancer, currently lacks targeted therapies and is associated with high recurrence rates in medical practice. In this study, the effectiveness of a specially developed magnetic nanodrug, namely doxorubicin (DOX)‐loaded Fe3O4 vortex magnetic nanoannulars coated with a cancer cell membrane (DOX‐VMAs@CM), against cancer under a varying low‐frequency magnetic field (MF), is investigated. This advanced nanodrug can specifically target and accumulate in tumors. Additionally, it considerably improves tumor suppression compared with that of DOX chemotherapy alone, indicating the possibility of homologous targeting of the cancer cell membrane and the vibrating effect of the MF. The DOX‐VMAs@CM nanoparticles (NPs) exhibit exceptional safety characteristics because of their ability to specifically target tumors. The results of RNA sequencing suggest that the potential mechanisms may involve cellular respiration, cell cycle, and ferroptosis regulation. Altogether, chemotherapy is successfully optimized by implementing a delivery system and MF intervention, and the developed DOX‐VMAs@CM NPs hold significant potential for use in the clinical treatment of TNBC. [ABSTRACT FROM AUTHOR]

Background and Purpose: Acute pancreatitis (AP) is associated with acinar cell death and inflammatory responses. Ferroptosis is characterized by an overwhelming lipid peroxidation downstream of metabolic dysfunction, in which NADPH‐related redox systems have been recognized as the mainstay in ferroptosis control. Nevertheless, it remains unknown how ferroptosis is regulated in AP and whether we can target it to restrict AP development. Experimental Approach: Metabolomics were applied to explore changes in metabolic pathways in pancreatic acinar cells (PACs) in AP. Using wild‐type and Ptf1aCreERT2/+IDH2fl/fl mice, AP was induced by caerulein and sodium taurocholate (NaT). IDH2 overexpressing adenovirus was constructed for infection of PACs. Mice or PACs were pretreated with inhibitors of FSP1 or glutathione reductase. Pancreatitis severity, acinar cell injury, mitochondrial morphological changes and pancreatic lipid peroxidation were analysed. Key Results: Unsaturated fatty acid biosynthesis and the tricarboxylic acid cycle pathways were significantly altered in PACs during AP. Inhibition of ferroptosis reduced mitochondrial damage, lipid peroxidation and the severity of AP. During AP, the NADPH abundance and IDH2 expression were decreased. Acinar cell‐specific deletion of IDH2 exacerbated acinar cell ferroptosis and pancreatic injury. Pharmacological inhibition of NADPH‐dependent GSH/GPX4 and FSP1/CoQ10 pathways abolished the protective effect of IDH2 overexpression on ferroptosis in acinar cells. CoQ10 supplementation attenuated experimental pancreatitis via inhibiting acinar cell ferroptosis. Conclusion and Implications: We identified the IDH2‐NADPH pathway as a novel regulator in protecting against AP via restricting acinar cell ferroptosis. Targeting the pathway and its downstream may shed light on AP treatment. [ABSTRACT FROM AUTHOR]

Background: Lung cancer (LC) occupies an important position in the lethality of cancer patients. Acquired resistance to gefitinib in lung adenocarcinoma (LUAD) seriously affects the therapeutic efficacy of LC. Thus, it is of major scientific and clinical significance to probe the mechanism of gefitinib resistance in LUAD for ameliorating the prognosis of patients. Methods: The expression of miRNAs in gefitinib-resistant LUAD cells was validated using qRT-PCR. Cell viability was assessed through CCK-8, whereas cell death was examined through PI staining. Changes in the ferroptosis process were evaluated by detecting the intracellular Glutathione (GSH), Malondialdehyde (MDA), and Reactive Oxygen Species (ROS) levels. Downstream targets of miR-138-5p were verified via luciferase reporter and RNA pull-down assays. RIP and qRT-PCR were employed to evaluate pri-miR-138-5p binding to DiGeorge critical region 8 (DGCR8) and the pri-miR-138-5p m6A modification level. Additionally, the impact of fat mass and obesity-associated protein (FTO) on LUAD gefitinib sensitivity was assessed in vivo by constructing a xenograft model. Results: We observed that miR-138-5p was notably diminished in gefitinib-resistant cells. Overexpression of miR-138-5p suppressed viability while facilitated cell death and intracellular ferroptosis in gefitinib-resistant cells. Moreover, lipocalin 2 (LCN2) was the downstream target of miR-138-5p. The biological functions of miR-138-5p on gefitinib-resistant cells was reversed by introduction of LCN2. FTO suppressed the binding of DGCR8 to pri-miR-138-5p through m6A modification, thereby restraining the processing of miR-138-5p. Meanwhile, silencing of FTO enhanced the sensitivity of LUAD to gefitinib treatment. Conclusion: FTO suppressed the processing of miR-138-5p and then modulated the proliferation, death, and ferroptosis of gefitinib-resistant cells through the miR-138-5p/LCN2 pathway, which may put forward novel insights for clinically ameliorating the therapeutic effect of gefitinib in LUAD. [ABSTRACT FROM AUTHOR]

Cancer, the world’s second leading cause of death after cardiovascular diseases, is characterized by hallmarks such as uncontrolled cell growth, metastasis, angiogenesis, hypoxia, and resistance to therapy. Autophagy, a cellular process that can both support and inhibit cancer progression, plays a critical role in cancer development and progression. This process involves the formation of autophagosomes that ultimately fuse with lysosomes to degrade cellular components. A key regulator of this process is Sirtuin 1 (SIRT1), which significantly influences autophagy. This review delves into the role of SIRT1 in modulating autophagy and its broader impacts on carcinogenesis. SIRT1 regulates crucial autophagy mediators, such as AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), effectively promoting or suppressing autophagy. Beyond its direct effects on autophagy, SIRT1’s regulatory actions extend to other cell death processes, including apoptosis and ferroptosis, thereby influencing tumor cell proliferation, metastasis, and chemotherapy responses. These insights underscore the complex interplay between SIRT1 and autophagy, with significant implications for cancer therapy. Targeting SIRT1 and its associated pathways presents a promising strategy to manipulate autophagy in cancer treatment. This review underscores the potential of SIRT1 as a therapeutic target, opening new avenues for enhancing cancer treatment efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Cisplatin is a widely used chemotherapeutic agent prescribed to treat solid tumors. However, its clinical application is limited because of cisplatininduced nephrotoxicity. A known complication of cisplatin is acute kidney injury (AKI). Deletion polymorphisms of GSTM1 and GSTT1, members of the glutathione S-transferase family, are common in humans and are presumed to be associated with various kidney diseases. However, the specific roles and mechanisms of GSTM1 and GSTT1 in cisplatin induced AKI remain unclear. Methods: To investigate the roles of GSTM1 and GSTT1 in cisplatin-induced AKI, we generated GSTM1 and GSTT1 knockout mice using CRISPR-Cas9 technology and assessed their kidney function under normal physiological conditions and cisplatin treatment. Using ELISA kits, we measured the levels of oxidative DNA and protein damage, along with MDA, SOD, GSH, and the GSH/GSSG ratio in wild-type and GSTM1/GSTT1 knockout mice following cisplatin treatment. Additionally, oxidative stress levels and the expression of ferroptosis-related proteins in kidney tissues were examined through Western blotting, qPCR, immunohistochemistry, and immunofluorescence techniques. Results: Here, we found that GSTT1 and GSTM1 were downregulated in the renal tubular cells of AKI patients and cisplatin-treated mice. Compared with WT mice, Gstm1/Gstt1-DKO mice were phenotypically normal but developed more severe kidney dysfunction and exhibited increased ROS levels and severe ferroptosis after injecting cisplatin. Discussion: Our study revealed that GSTM1 and GSTT1 can protect renal tubular cells against cisplatin-induced nephrotoxicity and ferroptosis, and genetic screening for GSTM1 and GSTT1 polymorphisms can help determine a standard cisplatin dose for cancer patients undergoing chemotherapy. [ABSTRACT FROM AUTHOR]

Aim: To target the reactive oxygen species (ROS) accumulation and renal tubular epithelial cell (rTEC) death in renal ischemia–reperfusion injury (IRI), we constructed a nanoparticle that offers ROS scavenging and rTEC-death inhibition: mesoporous zinc–tannic acid nanozyme (ZnTA). Materials & methods: After successfully constructing ZnTA, we proceeded to examine its effect on ROS accumulation, cellular ferroptosis and apoptosis, as well as injury severity. Results: Malondialdehyde, Fe2+ amounts and 4-HNE staining demonstrated that ZnTA effectively attenuated rTEC ferroptosis. TUNEL staining confirmed that Zn2+ carried by ZnTA could effectively inhibit caspase 3 and caspase 9, mitigating apoptosis. Finally, it reduced renal IRI through the synergistic effect of ROS scavenging and cell-death inhibition. Conclusion: This study is expected to provide a paradigm for a combined therapeutic strategy for renal IRI. Article highlights In this study, zinc–tannic acid nanozyme (ZnTA) was synthesized using natural plant polyphenol tannic acid. This study explored the morphological characteristics of ZnTA in detail. ZnTA has excellent reactive oxygen species scavenging effect. ZnTA was observed to effectively inhibit ferroptosis in both in vitro and in vivo experiments. The morphological characteristics of mitochondria after ZnTA treatment were examined using electron microscopy. Zn2+ in ZnTA inhibited the expression of caspase 3 and 9. Apoptosis inhibition was observed after ZnTA treatment. ZnTA can effectively alleviate renal IRI. [ABSTRACT FROM AUTHOR]

Myocardial ischemia-reperfusion injury is accompanied by ferroptosis mediated by reactive oxygen species and iron ions, which aggravates myocardial tissue damage. The present study aims to explore the molecular mechanism underlying the mitigating effects f PCSK9 on myocardial ischemia-reperfusion injury. MI/R rat model and OGD/R induced H9c2 model were established. The interaction between PCSK9 inhibitor and LRP8 was predicted by STRING database and verified by Immunoprecipitation assay experiment. CCK-8 kit results confirmed that PCSK9 inhibitor effectively protected against cardiomyocyte damage induced by OGD/R. TTC and histological examination via H&E staining revealed a significant alleviation of myocardial infarction and pathological alterations upon treatment with the PCSK9 inhibitor. Besides, DCFH-DA staining and biochemical kit results showed that PCSK9 inhibitor could regulate the changes of ferroptosis related indicators [ROS, iron level, MDA, SOD] and inhibit ferroptosis. Rescue experiments showed that PCSK9 inhibitors targeted LRP8 expression and inhibited GPX4/ROS-mediated ferroptosis in I/R-induced rats. Our study suggested that PCSK9 inhibitors could attenuate myocardial I/R injury, with the underlying mechanism intimately tied to the targeted modulation of LRP8/GPX4-mediated ferroptosis. [ABSTRACT FROM AUTHOR]

The p53 mutation is the most common genetic mutation associated with human neoplasia. TP53 missense mutations, which frequently arise early in breast cancer, are present in over thirty percent of breast tumors. In breast cancer, p53 mutations are linked to a more aggressive course of the disease and worse overall survival rates. TP53 mutations are mostly seen in triple-negative breast cancer, a very diverse kind of the disease. The majority of TP53 mutations originate in the replacement of individual amino acids within the p53 protein's core domain, giving rise to a variety of variations referred to as "mutant p53s." In addition to gaining carcinogenic qualities through gain-of-function pathways, these mutants lose the typical tumor-suppressive features of p53 to variable degrees. The gain-of-function impact of stabilized mutant p53 causes tumor-specific dependency and resistance to therapy. P53 is a prospective target for cancer therapy because of its tumor-suppressive qualities and the numerous alterations that it experiences in tumors. Phenotypic abnormalities in breast cancer, notably poorly differentiated basal-like tumors are frequently linked to high-grade tumors. By comparing data from cell and animal models with clinical outcomes in breast cancer, this study investigates the molecular mechanisms that convert gene alterations into the pathogenic consequences of mutant p53's tumorigenic activity. The study delves into current and novel treatment approaches aimed at targeting p53 mutations, taking into account the similarities and differences in p53 regulatory mechanisms between mutant and wild-type forms, as well. [ABSTRACT FROM AUTHOR]

Introduction: Triple-negative breast cancer (TNBC) is the most malignant type of breast cancer, and its prognosis is still the worst. It is necessary to constantly explore the pathogenesis and effective therapeutic targets of TNBC. Formononetin is an active ingredient with anti-tumor effects that we screened earlier. The main purpose of this study is to elucidate mechanism of the inhibitory effect of Formononetin on TNBC. Methods: We conducted experiments through both in vivo and in vitro methodologies. The in vivo experiments utilized a nude mice xenotransplantation model, while the in vitro investigations employed two breast cancer cell lines, MDA-MB-231 and MDA-MB-468. Concurrently, ferroptosis associated proteins, lipid peroxide levels, and proteins related to the rapamycin complex 1 were analyzed in both experimental settings. Results: In our study, Formononetin exhibits significant inhibitory effects on the proliferation of triple TNBC, both in vivo and in vitro. Moreover, it elicits an increase in lipid peroxide levels, downregulates the expression of ferroptosis-associated proteins GPX4 and xCT, and induces ferroptosis in breast cancer cells. Concurrently, Formononetin impedes the formation of the mammalian target of rapamycin complex 1 (mTORC1) and suppresses the expression of downstream Sterol regulatory element-binding protein 1(SREBP1). The utilization of breast cancer cells with SREBP1 overexpression or knockout demonstrates that Formononetin induces ferroptosis by modulating the mTORC1-SREBP1 signaling axis. Discussion: In conclusion, this study provides evidence that Formononetin exerts an anti-proliferative effect on triple-negative breast cancer by inducing ferroptosis. Moreover, the mTORC1-SREBP1 signal axis is identified as the primary mechanism through which formononetin exerts its therapeutic effects. These findings suggest that formononetin holds promise as a potential targeted drug for clinical treatment of TNBC. [ABSTRACT FROM AUTHOR]

Background and aim: Cholangiocarcinoma (CCA) is a rare cancer, yet its incidence and mortality rates have been steadily increasing globally over the past few decades. Currently, there are no effective targeted treatment strategies available for patients. ACLY (ATP Citrate Lyase), a key enzyme in de novo lipogenesis, is aberrantly expressed in several tumors and is associated with malignant progression. However, its role and mechanisms in CCA have not yet been elucidated. Methods: The expression of ACLY in CCA was assessed using transcriptomic profiles and tissue microarrays. Kaplan-Meier curves were employed to evaluate the prognostic significance of ACLY in CCA. Functional enrichment analysis was used to explore the potential mechanisms of ACLY in CCA. A series of assays were conducted to examine the effects of ACLY on the proliferation and migration of CCA cells. Ferroptosis inducers and inhibitors, along with lipid peroxide probes and MDA assay kits, were utilized to explore the role of ACLY in ferroptosis within CCA. Additionally, lipid-depleted fetal bovine serum and several fatty acids were used to evaluate the impact of fatty acids on ferroptosis induced by ACLY inhibition. Correlation analyses were performed to elucidate the relationship between ACLY and tumor stemness as well as tumor microenvironment. Results: The expression of ACLY was found to be higher in CCA tissues compared to adjacent normal tissues. Patients with elevated ACLY expression demonstrated poorer overall survival outcomes. ACLY were closed associated with fatty acid metabolism and tumor-initiating cells. Knockdown of ACLY did not significantly impact the proliferation and migration of CCA cells. However, ACLY inhibition led to increased accumulation of lipid peroxides and enhanced sensitivity of CCA cells to ferroptosis inducers. Polyunsaturated fatty acids were observed to inhibit the proliferation of ACLY-knockdown cells; nonetheless, this inhibitory effect was diminished when the cells were cultured in medium supplemented with lipid-depleted fetal bovine serum. Additionally, ACLY expression was negatively correlated with immune cell infiltration and immune scores in CCA. Conclusion: ACLY promotes ferroptosis by disrupting the balance of saturated and unsaturated fatty acids. ACLY may therefore serve as a potential diagnostic and therapeutic target for CCA. [ABSTRACT FROM AUTHOR]

As the main type of renal cell carcinoma (RCC), clear cell RCC (ccRCC) is often associated with the deletion or mutation of the von Hippel Lindau (VHL) gene, enhancement of glucose and lipid metabolism, and heterogeneity of the tumor microenvironment. VHL alterations in RCC cells lead to the activation of hypoxiainducible factors and their downstream target vascular endothelial growth factor, and to the reprogramming of multiple cell death pathways and metabolic weakness, including ferroptosis, which are associated with targeted therapy or immunotherapy. The changes in biological metabolites (e.g., iron and lipids) support ferroptosis as a potential therapeutic strategy for RCC, while iron metabolism and ferroptosis regulation have been examined as anti-RCC agents in numerous studies, and various ferroptosis-related molecules have been shown to be related to the metastasis and prognosis of ccRCC. For example, glutathione peroxidase 4 and glutaminase inhibitors can inhibit pyrimidine synthesis and increase reactive oxygen species levels in VHLdeficient RCC cells. In addition, the release of damage-associated molecular patterns by tumor cells undergoing ferroptosis also mediates antitumor immunity, and immune therapy can synergize with targeted therapy or radiotherapy through ferroptosis. However, Inducing ferroptosis not only suppresses cancer, but also promotes cancer development due to its potential negative effects on anti-cancer immunity. Therefore, ferroptosis and various tumor microenviroment-related molecules may co-occur during the development and treatment of RCC, and further understanding of the interactions, core targets, and related drugs of ferroptosis may provide new combination drug strategies for RCC treatment. Here we summarize the key genes and compounds on ferroptosis and RCC in order to envision future treatment strategies and to provide sufficient information for overcoming RCC resistance through ferroptosis. [ABSTRACT FROM AUTHOR]

The rapid expansion of the oncology field has revealed new insights into cell death processes, with a particular emphasis on the role of ferroptosis. Characterized by iron dependency and the accumulation of lipid peroxides and iron within cells, ferroptosis stands out as a unique form of programmed cell demise. This in-depth analysis delves into the pivotal role of IGF2BP3, an RNA-binding protein, in the complex regulatory network of ferroptosis in cancerous cells. By exerting post-transcriptional control over genes associated with iron equilibrium, IGF2BP3 is demonstrated to manage cellular iron concentrations and reactive oxygen species (ROS) equilibrium, thus affecting the destiny of the cell. The correlation between aberrant IGF2BP3 expression and increased aggressiveness, metastatic capacity, and poor prognosis in various cancers is further clarified. The potential of IGF2BP3 as a biomarker for prognosis and a therapeutic agent to enhance cancer cells' vulnerability to ferroptosis is also examined, heralding new strategies in cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) is a brain tumor characterized by the highest malignancy and the poorest prognoses. RNA binding motif single strand interacting protein 1 (RBMS1) has been implicated to be involved in various cancer progression. This study was conceived to explore the role and the mechanism of RBMS1 in GBM. Materials: RT-qPCR and western blot were used to evaluate RBMS1 expression and examine the transfection efficiency of sh-RBMS1. Cell proliferation was detected using CCK-8 assay and colony formation assay while cell apoptosis was detected with flow cytometry. Cell migration and invasion were detected with wound healing and transwell assay. The activities of MMP2 and MMP9 were detected using gelatin zymography. Western blot was used to measure proliferation-, apoptosis-, ferroptosis- and EMT-related proteins. Lipid peroxidation was detected with TBARS Assay Kit and lipid ROS was detected with a BODIPY 581/591 C11 kit. The total iron level was detected using corresponding assay kits. Results: According to GEPIA database, RBMS1 expression was upregulated in GBM and the present study found that RBMS1 expression was upregulated in GBM cells. After interfering RBMS1, GBM cell proliferation, migration, invasion and EMT process were inhibited while cell apoptosis and ferroptosis were promoted. However, ferroptosis inhibitor Fer-1 partially counteracted the protective effects of RBMS1 knockdown on GBM. Conclusion: Collectively, this study revealed that RBMS1 silence inhibited the malignant progression of GBM possibly through ferroptosis. [ABSTRACT FROM AUTHOR]

Sorafenib, a first-line therapeutic option for advanced hepatocellular carcinoma (HCC), faces a formidable challenge in the form of emerging resistance. Recently, the oncogene DDX11 antisense RNA 1 (DDX11-AS1) has been implicated in various cancers, including HCC. However, its role in sorafenib resistance remains unknown. Our findings reveal that DDX11-AS1 is upregulated in sorafenib-resistant HCC cells, contributing to their resistance by suppressing ferroptosis. Further investigation elucidated the mechanism by which DDX11-AS1 activates the antioxidant Nrf2-Keap1 pathway. By interacting with Nrf2 and hindering its association with Keap1, DDX11-AS1 enhances the stability and nuclear translocation of Nrf2. In summary, our study unveils the potent role of DDX11-AS1 as an enhancer of sorafenib resistance, inhibiting sorafenib-induced ferroptosis through the activation of the Nrf2-Keap1 pathway in HCC. These findings offer a promising therapeutic strategy to overcome resistance and effectively treat HCC. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a common autoimmune disease characterized primarily by persistent synovial inflammation and joint destruction. In recent years, ferroptosis, as a novel form of cell death, has garnered widespread attention due to its critical role in various diseases. This review explores the potential mechanisms of ferroptosis in RA and its relationship with the pathogenesis of RA, systematically analyzing the regulatory role of ferroptosis in synovial cells, chondrocytes, and immune cells. We emphasize the evaluation of ferroptosis-related pathways and their potential as therapeutic targets, including the development and application of inhibitors and activators. Although ferroptosis shows some promise in RA treatment, its dual role and safety issues in clinical application still require in-depth study. Future research should focus on elucidating the specific mechanisms of ferroptosis in RA pathology and developing more effective and safer therapeutic strategies to provide new treatment options for RA patients. [ABSTRACT FROM AUTHOR]

Objective: Notable progress has been made in “ferroptosis-based nano drug delivery systems (NDDSs)” over the past 11 years. Despite the ongoing absence of a comprehensive scientometric overview and up-to-date scientific mapping research, especially regarding the evolution, critical research pathways, current research landscape, central investigative themes, and future directions. Methods: Data ranging from 1 January 2012, to 30 November 2023, were obtained from the Web of Science database. A variety of advanced analytical tools were employed for detailed scientometric and visual analyses. Results: The results show that China significantly led the field, contributing 82.09% of the total publications, thereby largely shaping the research domain. Chen Yu emerged as the most productive author in this field. Notably, the journal ACS Nano had the greatest number of relevant publications. The study identified liver neoplasms, pancreatic neoplasms, gliomas, neoplasm metastases, and melanomas as the top five crucial disorders in this research area. Conclusion: This research provides a comprehensive scientometric assessment, enhancing our understanding of NDDSs focused on ferroptosis. Consequently, it enables rapid access to essential information and facilitates the extraction of novel ideas in the field of ferroptotic nanomedicine for both experienced and emerging researchers. [ABSTRACT FROM AUTHOR]

Resveratrol, a naturally occurring polyphenolic compound, has captivated the scientific community with its promising therapeutic potential across a spectrum of diseases. This review explores the complex role of resveratrol in modulating ferroptosis, a newly identified form of programmed cell death, and its potential implications for managing cardiovascular and cerebrovascular disorders, cancer, and other conditions. Ferroptosis is intricately linked to the pathogenesis of diverse diseases, with resveratrol exerting multifaceted effects on this process. It mitigates ferroptosis by modulating lipid peroxidation, iron accumulation, and engaging with specific cellular receptors, thereby manifesting profound therapeutic benefits in cardiovascular and cerebrovascular conditions, as well as oncological settings. Moreover, resveratrol’s capacity to either suppress or induce ferroptosis through the modulation of signaling pathways, including Sirt1 and Nrf2, unveils novel therapeutic avenues. Despite resveratrol’s limited bioavailability, advancements in molecular modification and drug delivery optimization have amplified its clinical utility. Future investigations are poised to unravel the comprehensive mechanisms underpinning resveratrol’s action and expand its therapeutic repertoire. We hope this review could furnish a detailed and novel insight into the exploration of resveratrol in the regulation of ferroptosis and its therapeutic prospects. [ABSTRACT FROM AUTHOR]

Background: Diabetic nephropathy (DN) has been a major factor in the outbreak of end-stage renal disease for decades. As the underlying mechanisms of DN development remains unclear, there is no ideal methods for the diagnosis and therapy. Objective: We aimed to explore the key genes and pathways that affect the rate progression of DN. Methods: Nanopore-based full-length transcriptome sequencing was performed with serum samples from DN patients with slow progression (DNSP, n = 5) and rapid progression (DNRP, n = 6). Results: Here, transcriptome proclaimed 22,682 novel transcripts and obtained 45,808 simple sequence repeats, 1,815 transcription factors, 5,993 complete open reading frames, and 1,050 novel lncRNA from the novel transcripts. Moreover, a total of 341 differentially expressed transcripts (DETs) and 456 differentially expressed genes (DEGs) between the DNSP and DNRP groups were identified. Functional analyses showed that DETs mainly involved in ferroptosis-related pathways such as oxidative phosphorylation, iron ion binding, and mitophagy. Moreover, Functional analyses revealed that DEGs mainly involved in oxidative phosphorylation, lipid metabolism, ferroptosis, autophagy/mitophagy, apoptosis/necroptosis pathway. Conclusion: Collectively, our study provided a full-length transcriptome data source for the future DN research, and facilitate a deeper understanding of the molecular mechanisms underlying the differences in fast and slow progression of DN. [ABSTRACT FROM AUTHOR]

Background: Ferroptosis, a non-apoptotic form of regulated cell death, plays a critical role in the suppression of various tumor types, including ovarian cancer. Artesunate (ART), a derivative of artemisinin, exhibits extensive antitumor effects and is associated with ferroptosis. This study aimed to investigate the mechanisms through which ART induces ferroptosis to inhibit ovarian cancer. Methods: RNA sequencing was conducted to identify differentially expressed genes associated with ART-induced ferroptosis. Dual-luciferase reporter assays and electrophoretic mobility shift assays were performed to confirm the interaction between Homeobox C11 (HOXC11) and the Prominin 2 (PROM2) promoter. Cell Counting Kit-8 (CCK-8) assays, flow cytometry, and wound healing assays were used to analyze the antitumor effects of ART. Western blot, biochemical assays and transmission electron microscope were utilized to further characterize ART-induced ferroptosis. In vivo, the effects of ART on ferroptosis were examined using a xenograft mouse model. Results: RNA sequencing analysis revealed that the HOXC11, PROM2 and Phosphatidylinositol 3-Kinase/ Protein Kinase B (PI3K/AKT) pathways were downregulated by ART. HOXC11 was found to regulate PROM2 expression by binding to its promoter directly. HOXC11 overexpression reversed ART-induced effects on ovarian cancer cell proliferation, migration, apoptosis and ferroptosis by activating the PROM2/PI3K/AKT signaling axis. Conversely, silencing PROM2 in HOXC11-overexpressing cells restored ART-induced ferroptosis and its associated antitumor effects by inhibiting the PI3K/AKT pathway. Consistently, in vivo studies using a xenograft mouse model confirmed that ART-induced tumor inhibition was mediated by ferroptosis through the suppression of the HOXC11/PROM2/PI3K/AKT pathway. Conclusion: This study identifies the HOXC11/PROM2/PI3K/AKT axis as a novel regulatory mechanism underlying ART-induced ferroptosis in ovarian cancer. Targeting the HOXC11/PROM2 axis may represent a promising therapeutic strategy for enhancing ferroptosis, offering new insights for the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Ferroptosis, distinct from apoptosis, necrosis, and autophagy, is a unique type of cell death driven by iron-dependent phospholipid peroxidation. Since ferroptosis was defined in 2012, it has received widespread attention from researchers worldwide. From a biochemical perspective, the regulation of ferroptosis is strongly associated with cellular metabolism, primarily including iron metabolism, lipid metabolism, and redox metabolism. The distinctive regulatory mechanism of ferroptosis holds great potential for overcoming drug resistance—a major challenge in treating cancer. The considerable role of nanobiotechnology in disease treatment has been widely reported, but further and more systematic discussion on how nanobiotechnology enhances the therapeutic efficacy on ferroptosis-associated diseases still needs to be improved. Moreover, while the exciting therapeutic potential of ferroptosis in cancer has been relatively well summarized, its applications in other diseases, such as neurodegenerative diseases, cardiovascular and cerebrovascular diseases, and kidney disease, remain underreported. Consequently, it is necessary to fill these gaps to further complete the applications of nanobiotechnology in ferroptosis. In this review, we provide an extensive introduction to the background of ferroptosis and elaborate its regulatory network. Subsequently, we discuss the various advantages of combining nanobiotechnology with ferroptosis to enhance therapeutic efficacy and reduce the side effects of ferroptosis-associated diseases. Finally, we analyze and discuss the feasibility of nanobiotechnology and ferroptosis in improving clinical treatment outcomes based on clinical needs, as well as the current limitations and future directions of nanobiotechnology in the applications of ferroptosis, which will not only provide significant guidance for the clinical applications of ferroptosis and nanobiotechnology but also accelerate their clinical translations. [ABSTRACT FROM AUTHOR]

The incorporation of mitochondria into early eukaryotes established organelle-based biochemistry and enabled metazoan development. Diverse mitochondrial biochemistry is essential for life, and its homeostatic control via mitochondrial dynamics supports organelle quality and function. Mitochondrial crosstalk with numerous regulated cell death (RCD) pathways controls the decision to die. In this review, we will focus on apoptosis and ferroptosis, two distinct forms of RCD that utilize divergent signaling to kill a targeted cell. We will highlight how proteins and processes involved in mitochondrial dynamics maintain biochemically diverse subcellular compartments to support apoptosis and ferroptosis machinery, as well as unite disparate RCD pathways through dual control of organelle biochemistry and the decision to die. Mitochondrial dynamics support organelle quality and function, which widely influences cellular biochemistry and signaling. In this review, Khatun et al. discuss the relationships between mitochondrial dynamics and two forms of regulated cell death, apoptosis and ferroptosis, to highlight critical interactions between these pathways that ultimately control the decision to die. [ABSTRACT FROM AUTHOR]

A paradigm shift in the study of cell death is currently occurring: whereas previously we had always considered that there were "points of no return" in any cell death pathway, we now realize that in many types of active, regulated cell death, this is not the case. We are also learning that cells that "almost die," but nevertheless survive, can transiently take on an altered state, with potential implications for understanding cancer therapies and relapse. In this perspective, we parse the many forms of cell death by analogy to suicide, sabotage, and murder, and consider how cells that might be "instructed" to engage a cell death pathway might nevertheless survive. In this perspective, Douglas Green discusses the many forms of cell death by analogy to suicide, sabotage, and murder and how cells that engage a cell death pathway might still survive. [ABSTRACT FROM AUTHOR]

BACKGROUND: It is of great significance to find new diagnostic markers of the disease and molecular targets for the treatment of the disease and the alleviation of organ injury. Ferroptosis is a newly discovered form of cell death. Overactivation of ferroptosis in animal models of sepsis is associated with the activation of inflammatory response and the injury of the liver, heart, kidney and other important organs, but the relationship between ferroptosis and bloodstream infection is not very clear OBJECTIVE: To study the changes and biological significance of ferroptosis in a mouse model of blood stream infection induced by different bacteria. METHODS: Blood stream infection models induced by gram negative bacteria Escherichia coli, Klebsiella pneumoniae and gram positive bacteria Staphylococcus aureus and Enterococcus faecalis were established in SPF-grade ICR male mice, with 42 mice in each group. The mRNA expression levels of ferroptosis marker genes transferrin receptor 1 and glutathione peroxidase 4 in the liver, myocardium and kidney were detected at 0.5, 1, 3, 6, 12, 24 and 48 hours after modeling. Another 18 SPF-grade ICR male mice were selected and randomly divided into dimethyl sulfoxide (DMSO) control group, DMSO+Klebsiella pneumoniae group, and Ferrostatin-1+Klebsiella pneumoniae group, with 6 mice in each group. In the latter two groups, animal models of Klebsiella pneumoniae bloodstream infection were established by tail vein injection of Klebsiella pneumoniae suspension, and 5 mg/kg Ferrostatin-1 and an equal dose of DMSO were given intraperitoneally 1 hour prior to the modeling of bloodstream infection, respectively. Serum levels of alanine aminotransferase, aspartate aminotransferase, blood creatinine, blood urea nitrogen, phosphocreatine kinase isoenzyme, lactate dehydrogenase, and mRNA expression levels of ferroptosis marker genes in various tissues were assayed at 6 hours after modeling. RESULTS AND CONCLUSION: After bloodstream infection modeling, the mRNA expression levels of transferrin receptor 1 in the liver, myocardium and kidney of bloodstream infection mice with different bacteria increased first and then decreased; and the mRNA expression level of glutathione peroxidase 4 decreased first, then increased, and reached the peak at 6 hours after modeling. The changes in transferrin receptor 1 and glutathione peroxidase 4 mRNA levels in bloodstream infection mice induced by gram-negative bacteria were more significant than those in blood stream infection mice induced by gram-positive bacteria, especially in bloodstream infection mice induced by Klebsiella pneumoniae. At 6 hours after bloodstream infection induced by Klebsiella pneumoniae, the levels of alanine aminotransferase, aspartate aminotransferase, serum creatinine, blood urea nitrogen, creatine phosphate kinase isoenzyme, lactate dehydrogenase in mice were significantly increased. Before modeling, Ferrostatin-1 intervention significantly reduced the levels of alanine aminotransferase, aspartate aminotransferase, serum creatinine, blood urea nitrogen, creatine phosphate kinase isoenzyme, and lactate dehydrogenase. All these findings indicate that the activation of ferroptosis in bloodstream infection mice induced by different bacteria is obvious, and the activation of ferroptosis in bloodstream infection mice induced by gram-negative bacteria is more obvious. Inhibition of iron death significantly attenuates liver, myocardial, and kidney injury in the mouse model of bloodstream infection induced by Klebsiella pneumoniae. [ABSTRACT FROM AUTHOR]

Peroxisomes are dynamic organelles involved in various cellular processes, including lipid metabolism, redox homeostasis, and intracellular metabolite transfer. Accumulating evidence suggests that peroxisomal homeostasis plays a crucial role in human health and disease, particularly in metabolic disorders and ferroptosis. The abundance and function of peroxisomes are regulated by a complex interplay between biogenesis and degradation pathways, involving peroxins, membrane proteins, and pexophagy. Peroxisome-dependent lipid metabolism, especially the synthesis of ether-linked phospholipids, has been implicated in modulating cellular susceptibility to ferroptosis, a newly discovered form of iron-dependent cell death. This review discusses the current understanding of peroxisome homeostasis, its roles in redox regulation and lipid metabolism, and its implications in human diseases. We also summarize the main mechanisms of ferroptosis and highlight recent discoveries on how peroxisome-dependent metabolism and signaling influence ferroptosis sensitivity. A better understanding of the interplay between peroxisomal homeostasis and ferroptosis may provide new insights into disease pathogenesis and reveal novel therapeutic strategies for peroxisome-related metabolic disorders and ferroptosis-associated diseases. [ABSTRACT FROM AUTHOR]

Background: Our previous study has demonstrated a decreased colonic CD8+CD39+ T cells, enrichment of granzyme A (GZMA), was found in pediatric-onset colitis and inflammatory bowel disease (IBD) characterized by impaired intestinal barrier function. However, the influence of GZMA on intestinal barrier function remains unknown. Methods: Western blotting(WB), real-time PCR (qPCR), immunofluorescence (IF) and in vitro permeability assay combined with intestinal organoid culture were used to detect the effect of GZMA on intestinal epithelial barrier function in vivo and in vitro. Luciferase, immunoprecipitation (IP) and subcellular fractionation isolation were performed to identify the mechanism through which GZMA modulated intestinal epithelial barrier function. Results: Herein, we, for the first time, demonstrated that CD8+CD39+ T cells promoted intestinal epithelial barrier function through GZMA, leading to induce Occludin(OCLN) and Zonula Occludens-1(ZO-1) expression, which was attributed to enhanced CDX2-mediated cell differentiation caused by increased glutathione peroxidase 4(GPX4)-induced ferroptosis inhibition in vivo and in vitro. Mechanically, GZMA inhibited intestinal epithelial cellular PDE4B activation to trigger cAMP/PKA/CREB cascade signaling to increase CREB nuclear translocation, initiating GPX4 transactivity. In addition, endogenous PKA interacted with CREB, and this interaction was enhanced in response to GZMA. Most importantly, administration of GZMA could alleviate DSS-induced colitis in vivo. Conclusion: These findings extended the novel insight of GZMA contributed to intestinal epithelial cell differentiation to improve barrier function, and enhacement of GZMA could be a promising strategy to patients with IBD. [ABSTRACT FROM AUTHOR]

Alkaline water is toxic to cultured aquatic animals that frequently live in pH-neutral freshwater. Overfishing and habitat destruction have contributed to the decline in the wild sturgeon population; consequently, the domestic hybrid sturgeon has become an increasingly important commercial species in China. Hybrid sturgeons are widely cultured in alkaline water, but little is known about the effects of alkalinity stress on hybrid sturgeon liver tissues. We exposed hybrid sturgeons to four alkaline concentrations (3.14 ± 0.02 mmol/L, 7.57 ± 0.08 mmol/L, 11.78 ± 0.24 mmol/L and 15.46 ± 0.48 mmol/L). Histopathology, biochemical index assessment, gene expression level detection and metabolomics analysis were used to investigate the negative effects on liver functions following exposure to NaHCO3. Livers exposed to alkaline stress exhibited severe tissue injury and clear apoptotic characteristics. With increased exposure concentrations, the hepatic superoxide dismutase, catalase, glutathione peroxidase and alkaline phosphatase activities significantly decreased in a dose-dependent manner. NaHCO3 exposure up-regulated the transcriptional levels of apoptosis/ferroptosis-related genes in livers. Similarly, the expression trends of interleukin-1β and heat shock protein genes also increased in high-alkalinity environments. However, the expression levels of complement protein 3 significantly decreased (p < 0.05). Hepatic untargeted metabolomics revealed the alteration conditions of various metabolites associated with the antioxidant response, the ferroptosis process and amino acid metabolism (such as beta-alanine metabolism; alanine, aspartate and glutamate metabolism; and glycine, serine and threonine metabolism). These data provided evidence that NaHCO3 impaired immune functions and the integrity of hybrid sturgeon liver tissues by mediating oxidative-stress-mediated apoptosis and ferroptosis. Our results shed light on the breeding welfare of domestic hybrid sturgeons and promote the economic development of fisheries in China. [ABSTRACT FROM AUTHOR]

The human phosphatase and tensin homolog (PTEN) is a tumor suppressor. A slight deficiency in PTEN might cause cancer susceptibility and progression. Infection by the liver fluke Clonorchis sinensis could lead to persistent loss of PTEN in cholangiocarcinoma. However, the mechanism of PTEN loss and its malignant effect on cholangiocarcinoma have not yet been elucidated. Extracellular vesicles secreted by Clonorchis sinensis (CS-EVs) are rich in microRNAs (miRNAs) and can mediate communication between hosts and parasites. Herein, we delved into the miRNAs present in CS-EVs, specifically those that potentially target PTEN and modulate the progression of cholangiocarcinoma via ferroptosis mechanisms. CS-EVs were extracted by differential ultra-centrifugation for high-throughput sequencing of miRNA. Lentiviral vectors were used to construct stably transfected cell lines. Erastin was used to construct ferroptosis induction models. Finally, 36 miRNAs were identified from CS-EVs. Among them, csi-miR-96-5p inhibited PTEN expression according to the predictions and dual luciferase assay. The CCK-8 assay, xenograft tumor assays and transwell assay showed that csi-miR-96-5p overexpression and PTEN knockout significantly increased the proliferation and migration of cholangiocarcinoma cells and co-transfection of PTEN significantly reversed the effect. In the presence of erastin, the cell proliferation and migration ability of the negative transfection control group were significantly impaired, although they did not significantly change with transfection of csi-miR-96-5p and PTEN knockout, indicating that they obtained ferroptosis resistance. Mechanistically, csi-miR-96-5p and PTEN knockout significantly inhibited ferroptosis through a decrease in ferrous ion (Fe2+) and malondialdehyde (MDA), and an increase in glutathione reductase (GSH), Solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). In conclusion, loss of PTEN promoted the progression of cholangiocarcinoma via the ferroptosis pathway and csi-miR-96-5p delivered by CS-EVs may mediate this process. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy for colorectal cancer (CRC) urgently needs low-toxicity and highly effective phytomedicine. Cepharanthine (Cep) shown to have multiple anti-tumor effects, including colorectal cancer, whose pivotal mechanisms are not fully understood. Herein, the present work aims to reveal the impact of Cep on the mitochondrial and anti-injury functions of CRC cells. Methods: The TOM70/20 expression was screened by bioinformatic databases. SW480 cells were utilized as the colorectal cancer cell model. The expression of TOM70/20 and the downstream molecules were measured by western blots (WB). The ferroptosis was analyzed using Transmission electron microscopy (TEM), C11-BODIPY, PGSK, and DCFH-DA probes, wherein the detection was performed by flow cytometry and laser confocal microscopy. The anti-cancer efficacy was conducted by CCK-8 and Annexin-V/PI assay. The rescue experiments were carried out using Fer-1 and TOM70 plasmid transfection. Results: Bioinformatic data identified TOM20 and TOM70 were highly expressed in colorectal cancer, which could be down-regulated by Cep. Further findings disclosed that Cep treatment destroyed the mitochondria and inactivated the NRF2 signaling pathway, an essential pathway for resistance to ferroptosis, thereby promoting reactive oxygen species (ROS) generation in CRC cells. As a result, prominent ferroptosis could be observed in CRC cells in response to Cep, which thereby led to the reduced cell viability of cancer cells. On the contrary, recovery of TOM70 dampened the Cep-elicited mitochondria damage, ferroptosis, and anti-cancer efficacy. Conclusion: In summary, Cep-mediated TOM inhibition inactivates the NRF2 signaling pathway, thereby triggering ferroptosis and achieving an anti-colorectal cancer effect. The current study provides an innovative chemotherapeutic approach for colorectal cancer with phytomedicine. [ABSTRACT FROM AUTHOR]

The ferroptosis genes associated with dermatomyositis are mined by bioinformatics to provide a new idea for clinical diagnosis and treatment of dermatomyositis. The dataset about dermatomyositis was screened from the comprehensive gene expression database, and the dataset was analyzed using R language. 261 differential genes of dermatomyositis were obtained, and 15 ferroptosis genes related to dermatomyositis were obtained after intersection with ferroptosis genes in FerrDb database. According to the Kyoto Encyclopedia of Genes and Genomes pathway, its role may be related to inflammation, ferroptosis, oxidative stress, and apoptosis. Based on protein-protein interaction network analysis and Cytoscape selected five key genes associated with dermatitis and ferroptosis. The potential of four diagnostic genes TIMP1, HMOX1, TFRC and CDK1A as biomarkers for the diagnosis and treatment of dermatomyositis is further identified through gene expression and receptor working characteristic curves, providing new insights into the mechanism of ferroptosis in dermatomyositis [ABSTRACT FROM AUTHOR]

One of the most critical axes for cell fate determination is how cells respond to excessive reactive oxygen species (ROS)--oxidative stress. Extensive lipid peroxidation commits cells to death via a distinct cell death paradigm termed ferroptosis. However, the molecular mechanism regulating cellular fates to distinct ROS remains incompletely understood. Through siRNA against human receptor-interacting protein kinase (RIPK) family members, we found that RIPK4 is crucial for oxidative stress and ferroptotic death. Upon ROS induction, RIPK4 is rapidly activated, and the kinase activity of RIPK4 is indispensable to induce cell death. Specific ablation of RIPK4 in kidney proximal tubules protects mice from acute kidney injury induced by cisplatin and renal ischemia/reperfusion. RNA sequencing revealed the dramatically decreased expression of acyl-CoA synthetase medium-chain (ACSM) family members induced by cisplatin treatment which is compromised in RIPK4-deficient mice. Among these ACSM family members, suppression of ACSM1 strongly augments oxidative stress and ferroptotic cell death with induced expression of ACS long-chain family member 4, an important component for ferroptosis execution. Our lipidome analysis revealed that overexpression of ACSM1 leads to the accumulation of monounsaturated fatty acids, attenuation of polyunsaturated fatty acid (PUFAs) production, and thereby cellular resistance to ferroptosis. Hence, knockdown of ACSM1 resensitizes RIPK4 KO cells to oxidative stress and ferroptotic death. In conclusion, RIPK4 is a key player involved in oxidative stress and ferroptotic death, which is potentially important for a broad spectrum of human pathologies. The link between the RIPK4-ASCM1 axis to PUFAs and ferroptosis reveals a unique mechanism to oxidative stress-induced necrosis and ferroptosis. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a multifactorial degenerative disease in the elder. Given the involvement of mammalian sterile 20-like kinase 1 (MST1) in PD, this article was to illustrate the mechanism of MST1 in 1-methyl-4-phenylpyridinium ion (MPP+)-induced PD cell model. Cells were treated with different concentrations of MPP+ to establish a PD cell model. Reverse transcription–quantitative polymerase chain reaction and Western blot revealed that MST1 expression and iron ion concentration increased, but cellular viability decreased with MPP+ concentration. Inhibition of MST1 decreased ferroptosis; increased cellular viability, iron ion content, and levels of glutathione peroxidase 4; and decreased reactive oxygen species and lactate dehydrogenase release. Upregulation of ferroptosis levels using ferroptosis agonist Erastin reduced the protective effect of MST1 inhibition on PD cells. Mechanistically, dual-luciferase analysis identified that miR-23b-3p targeted MST1 and inhibited its expression. Overexpression of miR-23b-3p inhibited MST1 levels, thereby reducing cellular ferroptosis and attenuating MPP+-induced cell injury. Collectively, MST1 expression increased with increasing MPP+ concentration, and miR-23b-3p targeted MST1 to reduce ferroptosis and MPP+-induced cell injury. [ABSTRACT FROM AUTHOR]

This paper elucidated the effects and mechanisms of aldehyde dehydrogenase 2 (ALDH2) on periodontitis. Rat model of periodontitis and periodontal ligament stem cell (PDLSC) model of periodontitis were constructed. PDLSC were transfected by ALDH2 overexpression vectors, and then treated by ML385 (Nrf2 inhibitor), ferrostatin-1 (ferroptosis inhibitor) and FIN56 (ferroptosis inducer), respectively. ALDH2, nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4) proteins was evaluated by immunohistochemistry and Western blot. Ferroptosis-related factors, including Fe2+ and glutathione (GSH), were assessed by commercial kits. Pro-inflammatory factors (interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]) and osteogenic differentiation-related proteins (osteocalcin [OCN] and runt-related transcription factor 2 [RUNX2]) were scrutinized by commercial kits and Western blot. In both periodontal tissues of periodontitis rats and PDLSC model of periodontitis, down-regulated ALDH2, Nrf2, GPX4 and GSH, but elevated Fe2+ level was discovered. ALDH2 overexpression in PDLSC resulted in an increase in Nrf2 expression. In PDLSC model of periodontitis, ALDH2 increased GPX4 and GSH levels, decreased Fe2+, IL-6 and TNF-α levels, and elevated OCN and RUNX2 expression. However, these effects of ALDH2 were counteracted by ML385. Additionally, the suppression of ALDH2 on IL-6 and TNF-α levels and promotion of it on OCN and RUNX2 expression in PDLSC model of periodontitis was further intensified by ferrostatin-1, but reversed by FIN56. ALDH2 may alleviate inflammation and facilitate osteogenic differentiation of PDLSC in periodontitis by hindering ferroptosis via activating Nrf2, suggesting it to be a promising candidate for treating periodontitis. [ABSTRACT FROM AUTHOR]

Cysteine desulfurase (NFS1) is highly expressed in a variety of tumors, which is closely related to ferroptosis of tumor cells and affects prognosis. The relationship between NFS1 and the development of gastric cancer (GC) remains unknown. Here we showed that NFS1 expression was significantly higher in GC tissues compared to adjacent normal tissues. Patients with high expression of NFS1 in GC tissues had a lower overall survival rate than those with low expression. NFS1 was highly expressed in cultured GC cells compared to normal gastric cells. Knockdown of NFS1 expression reduced the viability, migration and invasion of GC cells. In cultured GC cells, NFS1 deficiency promoted ferroptosis. Mechanistically, NFS1 inhibited ferroptosis by upregulating the signal transduction and activator of transcription 3 (STAT3) signaling pathway in cultured GC cells. NFS1 knockdown using siRNA inhibited the STAT3 pathway, reduced the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), and elevated intracellular levels of reactive oxygen species (ROS), ferrous ion (Fe2+), and malondialdehyde (MDA) in cultured GC cells. A specific STAT3 activator significantly reversed the inhibitory effect of NFS1 deficiency on ferroptosis in cultured GC cells. These in vitro results were further confirmed by experiments in vivo using a mouse xenograft tumor model. Collectively, these results indicate that NFS1 is overexpressed in human GC tissues and correlated with prognosis. NFS1 inhibits ferroptosis by activating the STAT3 pathway in GC cells. These results suggest that NFS1 may be a potential prognostic biomarker and therapeutic target to treat GC. [ABSTRACT FROM AUTHOR]

Dexmedetomidine (DEX) has been confirmed to exert neuroprotective effects in various nerve injury models by regulating ferroptosis, including spinal cord injury (SCI). Although it has been established that CDGSH iron sulfur domain 2 (CISD2) can regulate ferroptosis, whether DEX can regulate ferroptosis by CISD2 in SCI remains unclear. Lidocaine was used to induce PC12 cells and stimulate rats to establish SCI models in vitro and in vivo. MTT assays were performed to analyze cell viability. Ferroptosis was assessed by determining the levels of cellular reactive axygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and Fe2+. Ferritinophagy was analyzed by LysoTracker staining, FerroOrange staining, and immunofluorescence. Western blotting was carried out to quantify the levels of several proteins. Fluorescence microscopy was also used to observe cell autophagy. The morphology of mitochondria within the tissue was observed under transmission electron microscopy (TEM). DEX treatment weakened lidocaine-induced elevation of ROS, Fe2+, and MDA and reduced GSH in PC12 cells, indicating that DEX treatment weakened lidocaine-induced ferroptosis in PC12 cells. Similarly, lidocaine promoted autophagy, Fe2+, and microtubule-associated protein 1 light chain 3 (LC3) in PC12 cells and suppressed ferritin and p62 protein levels, indicating that DEX could weaken lidocaine-induced ferritinophagy in PC12 cells. DEX treatment improved the BBB score, reduced tissue damage, increased the number of neurons, and alleviated mitochondrial damage by inhibiting ferroptosis and ferritinophagy in lidocaine-induced SCI rat models. The decreased CISD2, ferritin heavy chain 1 (FTH1), solute carrier family 7-member 11-glutathione (SLC7A11), and glutathione peroxidase 4 (GPX4) protein levels and the elevated nuclear receptor coactivator 4 (NCOA4) protein levels in rat models in the lidocaine group were weakened by DEX treatment. Moreover, CISD2 inhibition reversed the inhibitory effects of DEX treatment on lidocaine-induced ferroptosis and ferritinophagy in PC12 cells significantly. Taken together, DEX treatment could impair lidocaine-induced SCI by inhibiting ferroptosis and ferritinophagy by upregulating CISD2 in rat models. [ABSTRACT FROM AUTHOR]

Background: Myocardial infarction (MI) induces complex transcriptional changes across diverse cardiac cell types. Single-cell RNA sequencing (scRNA-seq) provides an unparalleled ability to discern cellular diversity during infarction, yet the veracity of these discoveries necessitates confirmation. This investigation sought to elucidate MI mechanisms by integrating scRNA-seq and bulk RNA-seq data. Methods: Publicly available scRNA-seq (GSE136088) and bulk RNA-seq (GSE153485) data from mice MI models were analyzed. Cell types were annotated, and differential expression analysis conducted. Bulk RNA-seq underwent quality control, principal component analysis, and differential expression analysis. Results: In scRNA-seq data, the comparison between MI and sham groups unveiled a reduction in endothelial cell populations, but macrophages and monocytes increased. Within fibroblast subgroups, three distinct categories were discerned, with two exhibiting upregulation in MI. Notably, endothelial cells exhibited an elevated expression of genes associated with apoptosis and ferroptosis. In bulk RNA-seq analysis, distinct patterns emerged when comparing MI and sham groups. Specifically, six genes linked to endothelial ferroptosis exhibited heightened expression in MI group, thereby corroborating the scRNA-seq findings. Moreover, the examination of isolated cardiac macrophages from mice MI model revealed increased expression of Spp1, Col1a2, Col3a1, Ctsd, and Lgals3 compared to sham group, thus substantiating the dysregulation of macrophage apoptosis-related proteins following MI. Conclusion: MI altered the transcriptomic landscapes of cardiac cells with increased expression of apoptotic genes. Moreover, the upregulation of macrophage apoptosis marker was confirmed within MI models. The presence of endothelial cell depletion and ferroptosis in MI has been demonstrated. [ABSTRACT FROM AUTHOR]

Objective: Ischemic stroke is a leading cause of death and disability in individuals worldwide. Cerebral ischemia–reperfusion injury (CIRI) typically results in severe secondary injury and complications following reperfusion therapy. Microglia play critical roles in the inflammatory reaction of CIRI. However, less attention has been given to microglial death in this process. Our study aims to explore microglial death in CIRI and the effects and mechanism of minocycline treatment on microglia. Methods: A middle cerebral artery occlusion (MCAO) model was applied to induce CIRI in rats. At 0 h, 24 h and 48 h post-operation, rats were intraperitoneally injected with 45 mg/kg minocycline. Neurological deficit scoring, 2,3,5-triphenyltetrazolium chloride (TTC) staining, assessment of activated microglia and examination of mitochondrial structure were conducted and checked at 72 h after reperfusion. Additionally, an in vitro model of oxygen–glucose deprivation/reperfusion (OGD/R) model was established. BV-2 cells were treated with various pharmacological inhibitors of cell death or minocycline. Cell viability, lipid peroxidation, mitochondrial structure and function, and labile Fe2+ and ferroptosis-associated gene/protein levels were measured. Hemin was used for further validation after transcriptome analysis. Results: In the MCAO and OGD/R models, ferroptosis was identified as a major form of microglial death. Minocycline inhibited microglia ferroptosis by reducing HO-1 expression. In addition, minocycline improved mitochondrial membrane potential, mitochondrial structures and microglial survival in vivo. Minocycline also decreased labile Fe2+ levels, lipid peroxidation, and expression of ferritin heavy chain (FTH) and it improved mitochondrial structure and function in vitro. Upregulation of HO-1 counteracted the protective effect of minocycline. Conclusion: Ferroptosis is a major form of microglial death in CIRI. The protective mechanism of minocycline in CIRI partially hinges on its ability to effectively ameliorate microglia ferroptosis by downregulating HO-1 expression. Consequently, targeting microglia ferroptosis is a promising treatment for CIRI. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is caused by a variety of intrapulmonary and extrapulmonary factors and is associated with high morbidity and mortality. Oxidative stress is an important part of the pathological mechanism of ALI. Ferroptosis is a mode of programmed cell death distinguished from others and characterized by iron-dependent lipid peroxidation. This article reviews the metabolic regulation of ferroptosis, its role in the pathogenesis of ALI, and the use of ferroptosis as a therapeutic target regarding the pharmacological treatment of ALI. [ABSTRACT FROM AUTHOR]

Macroautophagy/autophagyis a lysosomal-regulated degradation process that participates incellular stress and then promotes cell survival or triggers celldeath. Ferroptosis was initially described as anautophagy-independent, iron-regulated, nonapoptotic cell death.However, recent studies have revealed that autophagy is positivelyassociated with sensitivity to ferroptosis. Nonetheless, themolecular mechanisms by which these two types of regulated cell death(RCD) modulate each other remain largely unclear. Here, we screened85 deubiquitinating enzymes (DUBs) and found that overexpression ofUSP13 (ubiquitin specific peptidase 13) could significantlyupregulate NFE2L2/NRF2 (NFE2 like bZIP transcription factor 2)protein levels. In addition, in 39 cases of KRAS-mutated lungadenocarcinoma (LUAD), we found that approximately 76% of USP13overexpression is positively correlated with NFE2L2 overexpression.USP13 interacts with and catalyzes the deubiquitination of thetranscription factor NFE2L2. Additionally, USP13 depletion promotesan autophagy-to-ferroptosis switch invitro andin xenograft tumor mouse models, through the activation of theNFE2L2-SQSTM1/p62 (sequestosome 1)-KEAP1 axis in KRAS mutant cellsand tumor tissues. Hence, targeting USP13 effectively switchedautophagy-to-ferroptosis, thereby inhibiting KRAS (KRASproto-oncogene, GTPase) mutant LUAD, suggesting the therapeuticpromise of combining autophagy and ferroptosis in the KRAS-mutantLUAD.Abbreviation: ACSL4: acyl-CoA synthetase long-chain family member 4; ACTB: actin beta; AL: autolysosomes; AP: autophagosomes; BCL2L1/BCL-xL: BCL2 like 1; CCK8: Cell Counting Kit-8; CQ: chloroquine; CUL3: cullin 3; DMSO: dimethyl sulfoxide; DOX: doxorubicin; DUB: deubiquitinating enzyme; Ferr-1: ferrostatin-1; GPX4: glutathione peroxidase 4; GSEA: gene set enrichment analysis; 4HNE: 4-hydroxynonenal; IKE: imidazole ketone erastin; KEAP1: kelch like ECH associated protein 1; KRAS: KRAS proto-oncogene, GTPase; LCSC: lung squamous cell carcinoma; IF: immunofluorescence; LUAD: lung adenocarcinoma; Lys05: Lys01 trihydrochloride; MAPK1/ERK2/p42: mitogen-activated protein kinase 1; MAPK3/ERK1/p44; MTOR: mechanistic target of rapamycin kinase; NFE2L2/NRF2: NFE2 like bZIP transcription factor, 2; NQO1: NAD(P)H quinone dehydrogenase 1; PG: phagophore; RCD: regulated cell death; RAPA: rapamycin; ROS: reactive oxygen species; SLC7A11/xCT: solute carrier family 7 member 11; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TUBB/beta-tubulin: tubulin, beta; UPS: ubiquitin-proteasome system; USP13: ubiquitin specific peptidase 13. [ABSTRACT FROM AUTHOR]

Purpose: Neratinib, a small-molecule tyrosine kinase inhibitor (TKI) that irreversibly binds to human epidermal growth factor receptors 1, 2 and 4 (HER1/2/4), is an approved extended adjuvant therapy for patients with HER2-amplified or -overexpressed (HER2-positive) breast cancers. Patients receiving neratinib may experience mild-to-severe symptoms of gut toxicity including abdominal pain and diarrhoea. Despite being a highly prevalent complication in gut health, the biological processes underlying neratinib-induced gut injury, especially in the colon, remains unclear. Methods: Real-time quantitative polymerase chain reaction (RT-qPCR) and histology were integrated to study the effect of, and type of cell death induced by neratinib on colonic tissues collected from female Albino Wistar rats dosed with neratinib (50 mg/kg) daily for 28 days. Additionally, previously published bulk RNA-sequencing and CRISPR-screening datasets on human glioblastoma SF268 cell line and glioblastoma T895 xenograft, and mouse TBCP1 breast cancer cell line were leveraged to elucidate potential mechanisms of neratinib-induced cell death. Results: The severity of colonic epithelial injury, especially degeneration of surface lining colonocytes and infiltration of immune cells, was more pronounced in the distal colon than the proximal colon. Sequencing showed that apoptotic gene signature was enriched in neratinib-treated SF268 cells while ferroptotic gene signature was enriched in neratinib-treated TBCP1 cells and T895 xenograft. However, we found that ferroptosis, but less likely apoptosis, was a potential histopathological feature underlying colonic injury in rats treated with neratinib. Conclusion: Ferroptosis is a potential feature of neratinib-induced colonic injury and that targeting molecular machinery governing neratinib-induced ferroptosis may represent an attractive therapeutic approach to ameliorate symptoms of gut toxicity. [ABSTRACT FROM AUTHOR]

Cystatin SN (CST1) appears to have pro-tumor effects in breast cancer (BC) and is involved in ferroptosis; however, there is no report on the regulation of ferroptosis by CST1 for BC development. The purpose of this study is to investigate the functions and mechanisms operated by CST1 in BC development and ferroptosis. Transcription Factor Activator Protein 2γ (TFAP2C) and CST1 levels in BC tissues and estrogen receptor (ER)+ cells were quantified by RT-qPCR and western blotting. After knocking down TFAP2C and CST1 expression in MCF7 and T47D cells, the proliferation, colony formation ability, apoptosis, and cell cycle were assessed. Ferroptosis was verified by detecting glutathione peroxidase 4 (GPX4) and 4-hydroxy-2-nonenal (4HNE) levels. The kits were used to test Fe2+, reactive oxygen species, malondialdehyde, and glutathione levels, and ultrastructure of mitochondria was observed through transmission electron microscope. Dual-luciferase reporter assay and chromatin immunoprecipitation test were carried out to investigate the interaction of TFAP2C and CST1. A transplanted tumor model was established to explore the function of TFAP2C in tumorigenesis by quantifying TFAP2C, CST1, Ki67, and GPX4 levels through western blotting and immunochemistry after silencing TFAP2C. TFAP2C and CST1 were predominantly expressed in BC cells. Silencing of TFAP2C or CST1 expression suppressed ER+ BC cell proliferation, promoted apoptosis and ferroptosis, and blocked cell cycle transition from G1 phase to S phase. TFAP2C knockdown in transplanted tumors inhibited tumor growth and GPX4 level. Upregulating CST1 nullified the anti-tumor effects of TFAP2C knockdown and TFAP2C promoted CST1 expression through transcription activation. TFAP2C activates CST1 transcription to facilitate BC development and block ferroptosis. [ABSTRACT FROM AUTHOR]

Approximately 80% of individuals encounter lower back pain (LBP), a prevalent clinical issue largely attributed to intervertebral disc degeneration (IDD). Ferroptosis is an iron-dependent lipid peroxidation-driven cell death, and there is growing evidence that ferroptosis plays an important role in various human diseases. However, the underlying mechanism of ferroptosis in IDD remains unclear. This study aims to reveal the potential hub genes and related pathways of ferroptosis in the pathogenesis and progression of IDD. In this study, we analyzed three microarray datasets from the GEO database. Additionally, we downloaded ferroptosis-related genes from FerrDb-V2 and extracted apoptosis-related genes from UniProt as a control to show the specificity of ferroptosis. Weighted gene co-expression network analysis (WGCNA) was performed to identify the IDD-related module genes. Then, ferroptosis-related genes and apoptosis-related genes were separately overlapped with the IDD-related module genes, resulting in the identification of 35 ferroptosis-related module genes (FRMG) and 142 apoptosis-related module genes (ARMG). Furthermore, we performed functional enrichment analysis and protein–protein interaction network, and Cytoscape along with CytoHubba was used to identify the hub genes. Finally, logistic regression models were constructed and identified two hub FRMGs (PTEN and EGFR) and one hub ARMG (CTNNB1), which could distinguish IDD patients from controls (P < 0.05). The areas under the ROC curves were 0.792 and 0.730, respectively, suggesting that ferroptosis is more specific than apoptosis in IDD. In conclusion, this study provided fresh perspectives on ferroptosis in the pathogenesis and progression of IDD that can be used to evaluate potential biomarker genes and therapeutic targets. [ABSTRACT FROM AUTHOR]

Ferroptosis is a new way of cell death which is reported to participate in the pathology of myocardial ischemia–reperfusion (MI/R) injury, but it's mechanism remains unclear. The present investigation is to study the emerging role of long non-coding RNA (lncRNA) regulator of reprogramming (ROR) in cardiomyocyte ferroptosis after hypoxia/reoxygenation (H/R) administration. RT-qPCR and/or Western blot methods were performed to examine the gene/or protein levels, and CCK-8, ELISA, and DCFH-DA staining determined the cellular viability and ferroptosis. Dual-luciferase and RNA immunoprecipitation were applied to verify molecular interaction. LncRNA ROR and miR-769-5p were overexpressed and reduced in blood samples from MI patients and H/R-treated AC16 cells, respectively. Mechanistically, lncROR sponged to miR-769-5p, thus upregulating CBX7 expression. Functional experiments presented that lncRNA ROR silence mitigated H/R-stimulated inflammatory damage, oxidative stress, and ferroptosis in AC16 cells, whereas these roles could be reversed by co-downregulation of miR-769-5p or co-overexpression of CBX7. These data uncovered that lncRNA ROR prevented against H/R-induced cardiomyocyte ferroptosis by modulating miR-769-5p/CBX7 signaling, emphasizing the therapeutic value of lncRNA ROR in MI/R injury. [ABSTRACT FROM AUTHOR]