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Hepatocellular carcinoma (HCC) is a significant global health issue, ranking as the sixth most prevalent malignancy and the fourth leading cause of cancer-related mortality worldwide. Despite advancements in therapeutic strategies, mortality rates for HCC remain high. The tumor immune microenvironment (TIME) plays a vital role in HCC progression by influencing tumor cell survival and growth. Recent studies highlight the essential role of exosomes in mediating intercellular communication within the TIME, particularly in interactions among tumor cells, immune cells, and fibroblasts. These interactions drive critical aspects of tumor development, including immune escape, angiogenesis, drug resistance, and metastasis. A detailed understanding of the molecular mechanisms by which exosomes modulate the TIME is essential for developing targeted therapies. This review systematically evaluated the roles and regulatory mechanisms of exosomes within the TIME of HCC, examining the impact of both HCC-derived and non-HCC-derived exosomes on various cellular components within the TIME. It emphasized their regulatory effects on cell phenotypes and functions, as well as their roles in HCC progression. The review also explored the potential applications of exosome-based immunotherapies, offering new insights into improving therapeutic strategies for HCC., Competing Interests: JWPY has been an Editorial Board Member of Journal of Clinical and Translational Hepatology since 2021. The other authors have no conflict of interests related to this publication., (© 2025 Authors.)

Stimulator of interferon response cGAMP interactor 1 (STING1), as an innate immune adaptor protein that mediates DNA sensing, has attracted tremendous biomedical interest. However, several recent researches have revealed the key role of STING1 in regulating the metabolic pathway. Here, we investigated its role in adipocyte differentiation. Preadipocytes with lentivirus-mediated Sting1 knockdown or overexpression were constructed to examine the effect of STING1 on adipocyte differentiation in vitro. Proteomics was performed in adipocytes to explore the mechanisms by which STING1 exerts pro-adipogenesis effects. Coimmunoprecipitation (CoIP)/mass spectrometry (MS) assay were used to identify the interacting partners of STING1. Our results showed that STING1 was upregulated during adipogenic differentiation of 3T3-L1 and white adipose tissue-derived stromal vascular precursor cells (WAT-SVF), accompanied by upregulation of adipocyte marker genes, peroxisome proliferator-activated receptor gamma (Pparg) and CCAAT/enhancer-binding protein beta (Cebpβ). Knockdown or overexpression of Sting1 altered adipogenesis in adipocytes. Mechanistically, proteomics and CoIP/MS assay revealed that STING1 targets non-muscle myosin protein (MYH9) to block its expression, which enhances AKT/GSK3β signaling and mediates β-catenin accumulation, affecting adipogenesis-related genes in adipocytes. These findings suggest that STING1 targeting combined with MYH9 regulates adipocyte differentiation through the AKT/GSK3β/β-catenin pathway. This is a new potential target for the treatment of hypertrophic adipose tissue, or obesity., 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.)

WBP1L is a broadly expressed transmembrane adaptor protein involved in regulating hematopoietic stem cell function and T cell development. It interacts with NEDD4-family E3 ubiquitin ligases and regulates important chemokine receptor CXCR4. Using tandem affinity purification coupled with mass spectrometry, we identified novel WBP1L interactions with the IFNγ receptor and the Cullin-RING ubiquitin ligases CRL1 β-TrCP1/2 . We found that WBP1L interaction with the IFNγ receptor serves to downregulate proximal IFNγ receptor signaling in female macrophages, while the interaction with CRL1 β-TrCP1/2 ubiquitin ligases regulates WBP1L protein levels. Disrupting this interaction, as well as inhibiting proteasome activity or neddylation, increased WBP1L protein levels, demonstrating that CRL1 β-TrCP1/2 ubiquitin ligases regulate WBP1L protein abundance. These data provide important insights into the mechanisms controlling WBP1L function., 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.)

Pulmonary arterial hypertension (PAH) is a syndrome characterized by increased pulmonary vascular resistance and elevated pulmonary artery pressure, ultimately leading to right heart failure and even death. Increasing evidence implicates the fat mass and obesity-associated protein (FTO) in various metabolic and inflammatory pathways; however, its role in pulmonary endothelial function and PAH remains largely unexplored. In this study, we examined the effects of endothelial cell-specific FTO knockout on PAH development. Our results indicate that the absence of FTO in endothelial cells mitigates hypoxia-induced PAH. Mechanistically, FTO deletion reduces endothelial cell adhesion and inflammatory cell infiltration. Single-cell RNA sequencing revealed disruptions in key inflammatory and adhesion pathways, including TNF-α/NF-κB signaling and VCAM1 expression. These findings suggest that targeting endothelial FTO could be a novel therapeutic strategy for PAH by modulating endothelial adhesion and inflammatory responses., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest regarding the publication of this article. All authors have contributed to the work and have approved the final version of the manuscript. The research was conducted without commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Autologous fat grafting is a widely used technique in plastic and reconstructive surgery, but its efficacy is often limited by the poor survival rate of transplanted adipose tissue. This study aims to enhance the survival of fat grafts by investigating the role of thymosin beta-4 (Tβ4) in facilitating mitochondrial transfer from adipose-derived stem cells (ADSCs) to adipocytes and newly formed blood vessels within the grafts via tunneling nanotubes (TNTs). We demonstrate that Tβ4 upregulates the Rac/F-actin pathway, leading to an increased formation of TNTs and subsequent transfer of mitochondria from ADSCs. This process mitigates oxidative stress, reduces apoptosis, and promotes revascularization, thereby improving the quality and volume retention of fat grafts. Our findings provide a novel mechanistic insight into the enhancement of fat graft survival and suggest that mitochondrial transplantation and Tβ4 are potential therapeutic strategies to improve clinical outcomes in autologous fat transfer procedures., Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists., (Copyright © 2025 Elsevier Inc. All rights reserved.)

The occurrence and progression of traumatic brain injury involve a complex process. The pathophysiological mechanisms triggered by neuronal damage include various forms of programmed cell death, including ferroptosis. We observed upregulation of TNFAIP3 in mice after traumatic brain injury. Overexpression of TNFAIP3 inhibits HT-22 proliferation and cell viability through ferroptosis. Mechanistically, TNFAIP3 interacts with the HMOX1 protein and promotes its stability through the deubiquitination pathway. Additionally, TNFAIP3 can enhance lipoperoxidation, mitochondrial damage, and neuronal cell death by promoting ACSL3 degradation via NEDD4-mediated ubiquitination. Mice injected with AAV-shTNFAIP3 exhibited reduced neuronal degeneration and improved motor and cognitive function following cortical impact injury. In conclusion, our findings demonstrate that TNFAIP3 deficiency inhibits neuronal cell ferroptosis and ameliorates cognitive impairment caused by traumatic brain injury and demonstrate its potential applicability in the treatment of traumatic brain injury., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Elevated synovial expression of the triggering receptor expressed on myeloid cells 1 (TREM1) has been identified as a significant biomarker for assessing disease activity in rheumatoid arthritis (RA). The upregulated expression of TREM1, induced by inflammatory mediators in infiltrating macrophages, plays a critical role in synovitis and joint destruction in RA. Our previous sequencing data linked TREM1 activation to aberrant mitophagy. Thus, we explored the efficacy of targeting TREM1 in treating experimental arthritis and its regulatory effect on mitophagy. TREM1 signalling activation was assessed via TREM1, DAP12, and p-SYK levels, and mitophagy was measured through PINK1, PARKIN, and LC3A/B levels. In vitro, TREM1-overexpressing RAW264.7 cells were generated, and the differences in expression and pathways were analyzed via RNA-seq. Changes in the number and morphology of mitochondria and mitophagy in TREM1-overexpressing RAW264.7 cells and normal control were observed via transmission electron microscopy, MitoTracker confocal microscopy and mitochondrial membrane potential analysis. The promotion of TOMM40 gene transcription by TREM1-activated E2F1 was determined via ChIP-PCR and E2F1 siRNA. We found that TREM1 was highly expressed and activated in the synovial tissues of CIA mice concomitant with abnormal mitophagy. The mitochondrial outer membrane transporter TOMM40 was upregulated in experimental arthritis, and the protein levels of PINK1 and LC3B were decreased. RNA-seq analysis indicated that mitophagy-related proteins were extensively downregulated and that the transcription factor E2F1 and the mitochondrial outer membrane transporter TOMM40 were significantly upregulated in TREM1-overexpressing cells. ChIP-PCR revealed that TREM1 overexpression significantly promoted the interaction between E2F1 and TOMM40 gene in RAW264.7 cells. E2F1 knockdown markedly reversed TOMM40 upregulation, mitophagy injury and ROS production in TREM1-overexpressing macrophages but not in control cells. Our study provides preliminary evidence that E2F1 regulates TOMM40 transcription and disrupts mitophagy flux in TREM1-activated macrophages. Inhibiting TREM1 effectively mitigated experimental arthritis by restoring macrophage mitophagy and reducing intracellular ROS levels., Competing Interests: Competing interests Hai Li was supported by the Shanghai Municipal Health Commission [grant number 202140121]. Zhen-Zhen Dai was supported by the Shanghai Municipal Health Commission [grant number 20244Y0199] and Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine [grant number FH2024G004]., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Enzymatically formed side-chain oxysterols function as signaling molecules regulating cholesterol homeostasis and act as intermediates in the biosynthesis of bile acids. In addition to these physiological functions, an imbalance in oxysterol homeostasis has been implicated in pathophysiology. Cholesterol 25-hydroxylase (CH25H) and its product 25-hydroxycholesterol (25-OHC), also formed by autoxidation, are associated with amyotrophic lateral sclerosis. However, the effects of 25-OHC on cell viability in glial cells remain unclear. This study demonstrates that 25-OHC induces ferroptosis, an iron-dependent programmed cell death, in mouse Schwann IMS32 cells. Mechanistically, 25-OHC suppressed the expression of selenoprotein glutathione peroxidase 4 (GPX4) at both the transcriptional and translational levels by inhibiting the processing of sterol regulatory element-binding proteins (SREBPs). In addition, 25-OHC upregulated the expression of NADH-cytochrome b5 reductase 1 (CYB5R1) and NADPH-cytochrome P450 reductase (POR), enzymes that promote lipid peroxidation. We further found that 25-OHC increases the expression of glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) and decreases glutathione levels. Importantly, non-cytotoxic concentrations of 25-OHC enhanced cellular sensitivity to ferroptosis inducers by downregulating GPX4 expression. These findings reveal a multifaceted approach whereby 25-OHC induces ferroptosis through SREBP pathway suppression and redox imbalance in mouse Schwann IMS32 cells., Competing Interests: Declarations of interest None., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) remains a principal factor in neurological disorders, often resulting in significant morbidity due to secondary neuroinflammatory and oxidative stress responses. While circular RNAs are recognized for their high expression levels in the nervous system and play crucial roles in various neurological processes, their specific contributions to the pathophysiology of TBI remain underexplored. In this study, the possible molecular mechanisms through which circMETTL9 modulated oxidative stress and neurological outcomes following TBI were investigated. In vitro model of oxidative stress utilizing SH-SY5Y cells revealed that circMETTL9 knockdown significantly attenuated H₂O₂-induced reactive oxygen species (ROS) production, reduced apoptosis, and preserved mitochondrial function. Additionally, CCAR2 has been identified as a circMETTL9-binding protein by mass spectrometry and RNA immunoprecipitation, with circMETTL9 positively regulating CCAR2 expression. Meanwhile, on the basis of silencing CCAR2, it was verified that the regulation of oxidative stress in SH-SY5Y cells by circMETTL9 was mediated by CCAR2. In vivo experiments using a TBI rat model further confirmed that CCAR2 knockdown alleviated central nervous system (CNS) injury, reduced oxidative stress and apoptosis, and protected mitochondrial integrity following TBI. These findings suggest a novel mechanism by which circMETTL9 targets CCAR2 via mitochondria-mediated Bax/Bcl-2/caspase-3 signaling to regulate apoptosis. CircMETTL9 may provide a viable therapeutic target for mitigating neurological dysfunction following TBI, offering new insights into potential interventions aimed at reducing secondary brain 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. Published by Elsevier Inc.)

Angiogenesis, the process of new blood vessel formation, involves endothelial cell proliferation and migration, accompanied by the remodeling of the extracellular matrix (ECM). Type IV collagen, a major ECM component, plays a critical role in vascular basement membrane regeneration, influencing cell polarity, migration, and survival. This study examines the regulatory role of Notch signaling, mediated by Notch3, in type IV collagen expression using TIG-1 fibroblasts and a co-culture angiogenesis model with human umbilical vein endothelial cells (HUVECs). Using small interfering RNA (siRNA) to suppress Notch3 expression, we observed a significant reduction in COL4A1 gene expression, which encodes the α1 chain of type IV collagen. Conversely, transient expression of the Notch3 intracellular domain (NICD3) activated Notch signaling, resulting in increased COL4A1 expression. In the co-culture model, pre-treatment of TIG-1 cells with Notch signaling inhibitors, including siNotch3 and DAPT, decreased the number of α1(IV)-positive TIG-1 fibroblasts adjacent to HUVECs. This reduction highlights the essential role of Notch3-mediated signaling in promoting type IV collagen expression during angiogenesis. Our findings suggest that Notch signaling regulates type IV collagen expression levels, supporting basement membrane formation and vascular maturation. These results provide insight into the molecular mechanisms of angiogenesis, potentially contributing to therapeutic strategies targeting vascular-related pathologies., 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.)

Ovarian cancer remains a significant challenge due to the lack of effective treatment and the resistance to conventional therapies. Ferroptosis, a form of regulated cell death characterized by iron-depend and lipid peroxidation, has emerged as a potential therapeutic target in cancer. Ovarian cancer has been reported to exert an "iron addiction" phenotype which makes it is susceptible to ferroptosis inducers. However, we found here that high-adhesion ovarian cancer cells were resistant to ferroptosis. Mechanistically, by PCR array, we identified junctional adhesion molecule 3 (JAM3) as a key mediator of ferroptosis resistance in high-adhesion ovarian cancer cells. Knockdowning and blocking JAM3 sensitized cancer cells to ferroptosis inducers RSL3 and erastin, while JAM3 overexpression conferred resistance to these agents. In addition, JAM3 also promoted ovarian cancer cells resistance to chemotherapeutic agent cisplatin in vitro and in vivo by inhibiting ferroptosis. Furthermore, we demonstrated that JAM3 promoted ferroptosis resistance through NRF2-induced upregulation of FSP1, a critical suppressor of lipid peroxidation. Inhibition of the NRF2/FSP1 pathway eliminated high-adhesion, JAM3 overexpressed ovarian cancer cells resistance to ferroptosis, and decreased cancer cells resistance to cisplatin. Moreover, JAM3 high expression was associated with poor prognosis in patients with ovarian cancer. Altogether, this study provided novel insights into the molecular mechanisms underlying ferroptosis resistance and identify JAM3 as a potential therapeutic target for combating drug resistance in ovarian cancer., Competing Interests: Declaration of competing interest The authors declare no conflict of interests that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

BMP-9 and BMP-10 are TGF-β family signaling ligands naturally secreted into blood. They act on endothelial cells and are required for proper development and maintenance of the vasculature. In hereditary hemorrhagic telangiectasia, regulation is disrupted due to mutations in the BMP-9/10 pathway, namely in the type I receptor ALK1 or the co-receptor endoglin. It has been demonstrated that BMP-9/10 heterodimers are the most abundant signaling species in the blood, but it is unclear how they form. Unlike other ligands of the TGF-β family, BMP-9 and -10 are secreted as a mixture of disulfide-linked dimers and monomers, in which the interchain cysteine (Cys-392) remains either paired or unpaired. Here, we show that the monomers are secreted in a cysteinylated form that crystallizes as a non-covalent dimer. Despite this, monomers do not self-associate at micromolar or lower concentrations and have reduced signaling potency compared to disulfide-linked dimers. We further show using protein crystallography that the interchain disulfide of the BMP-9 homodimer adopts a highly strained syn-periplanar conformation. Hence, geometric strain across the interchain disulfide is responsible for infrequent interchain disulfide bond formation, not the cysteinylation. Additionally, we show that interchain disulfide bond formation occurs less in BMP-9 than BMP-10 and these frequencies can be reversed by swapping residues near the interchain disulfide that form attractive interactions with the opposing protomer. Finally, we discuss the implications of these observations on BMP-9/10 heterodimer formation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: “A. Henrickson is an employee of Beckman Coulter Life Sciences. None of the other authors have any conflicts of interest.”., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: Vertebrates vary greatly in their abilities to regenerate injured hearts. Zebrafish possess a remarkable capacity for cardiac regeneration, making them an excellent model for regeneration research. Recent studies have reported the activation and underlying regulatory mechanisms of leptin b (lepb) and the leptin b-linked enhancer (LEN) in injured hearts. However, the regenerative response activity of the leptin receptor (lepr) and its regulatory mechanisms still warrant further exploration., Materials and Methods: We identified a novel lepr-linked enhancer (leprEnh) and generated a stable transgenic zebrafish line for validation. We also employed a genetic ventricle ablation system to elucidate the mechanisms governing its activation. Immunofluorescence, in situ hybridization and confocal imaging of larvae treated with various inhibitors during ventricle regeneration were performed., Key Findings: Our results revealed that both lepr expression and leprEnh-directed EGFP fluorescence were weakly expressed in the ventricle during early heart development but displayed a sharp increase after ventricle ablation. Strong injury response activity was also observed in the atrium. Furthermore, the regeneration-responsive activity was attenuated by hemodynamic force alteration and was modulated by Notch, ErbB2 and BMP signaling pathways., Significance: Our study sheds light on the regulation of lepr and leprEnh during heart regeneration and provide a basis for screening for novel therapeutic targets for myocardial infarction., 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.)

Congenital diaphragmatic hernia (CDH) is characterized by incomplete formation of the diaphragm, causing herniation of the abdominal organs and subsequent lung hypoplasia; however, the etiology of CDH is poorly understood. The Retinoid Hypothesis posits that abnormal retinoic acid signaling leads to the formation of diaphragmatic hernias. Our goal is to better understand diaphragm development and the etiology of CDH. To achieve this goal, we first performed single-cell RNA sequencing analysis of the developing diaphragm, then generated a conditional retinoic acid receptor dominant negative knock-in to inhibit retinoic acid signaling in the mesenchyme of the developing diaphragm. Our single-cell RNA sequencing analysis revealed 10 distinct cell populations in the developing diaphragm, with mesenchymal cells being the primary expresser of CDH and retinoic acid signaling-related genes. Transgenic inhibition of mesenchymal retinoic acid signaling in the developing diaphragm caused hernias in 100% of embryos, recapitulating the hallmarks of CDH. Overall, our studies show that retinoic acid signaling in the mesenchymal component of the diaphragm is required for normal diaphragm development., (© 2025 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Polycystic ovary syndrome (PCOS) is a common disorder that affects the female reproductive system, with an incidence of 8 % to 15 %. It is characterized by irregular menstruation, hyperandrogenemia, and polycystic abnormalities in the ovaries. Nevertheless, there is still much to learn about the molecular pathways underlying PCOS. Apoptosis is the process by which cells actively destroy themselves, and it is vital to an organism's ability to develop normally and maintain homeostasis. In recent years, a growing body of research has indicated a connection between the pathophysiology of PCOS and apoptosis. Therefore, it is critical to comprehend the relationship between PCOS and apoptosis in greater detail, identify the pathophysiological underpinnings of PCOS, and provide fresh perspectives and targets for its treatment. This review aims to summarize the relationship between PCOS and apoptosis, discuss how apoptosis affects normal ovarian function and how it becomes dysfunctional in the ovaries of PCOS patients, and investigate the signaling pathways associated with apoptosis in PCOS, including PI3K-Akt, TNF, NF-κB, and p53. Additionally, potential therapeutic approaches for PCOS treatment are provided by summarizing the role of apoptosis in PCOS therapy., Competing Interests: Declaration of competing interest None declared., (Copyright © 2025. Published by Elsevier Inc.)

Aims: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) with key pathologic processes including myocardial necrosis, fibrosis, inflammation, and hypertrophy, which are involved in heart failure (HF), stroke, and even sudden death. Our aim was to explore the communication network among various cells in the heart of transverse aortic constriction (TAC) surgery induced HCM mice., Materials and Methods: Single-cell RNA-seq data of GSE137167 was downloaded from the Gene Expression Omnibus (GEO) database. Seurat was used to perform the standard workflow. CellChat was utilized to compute the cell-cell interaction network and analyze the ligand-receptor pairs. Weighted gene co-expression network analysis (WGCNA) was conducted to identify gene co-expression modules. In vitro and in vivo studies were performed to verify bioinformatic analysis findings through real-time quantitative PCR (RT-qPCR), Edu staining, transwell assay, western blot, immunofluorescence assay, CCK-8, hematoxylin and eosin (H&E) staining, and echocardiography based on TAC mouse model., Key Findings: Our results showed that after TAC surgery, the interaction between cardiac fibroblasts and macrophages was very common, and the increasing pleiotrophin (PTN) ligand secreted by cardiac fibroblasts could promote the self-proliferation or invasion for myocardial fibrosis as well as stimulate the inflammatory response of macrophages to contribute TAC surgery induced HCM through acting on Syndecan 4 (SDC4) receptor., Significance: Our study demonstrates that PTN derived from cardiac fibroblasts may play potential role in pressure overload-induced HCM through activating the PTN-SDC4 pathway in cardiac fibroblasts and macrophages, which may be a potential therapeutic target for pressure overload-induced HCM patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Tumor cells are known to enhance glycolysis, even under normoxic conditions, via the Warburg effect, producing excess lactic acid in the tumor microenvironment. Lactic acid enhances the IL-23/IL-17 pathway and induces chronic inflammation. The acidic microenvironment formed by lactic acid suppresses immune cell proliferation and activation. In the present study, we clarified that lactic acid had two novel activities for immune cells. First, lactic acid specifically enhanced acetylation at lysine 27 of histone H3 (H3K27ac) in splenic B cells and monocytes/macrophages, and this epigenetically up-regulates the expression of genes. Acetylation and methylation of other residues of histone H3 were rarely induced. Second, lactic acid induced a particularly-marked enhancement of Il10 gene expression in B cells, leading to an increase in IL-10-producing regulatory B (Breg) cells. Furthermore, two pathways should be involved in both the enhancement of H3K27ac and the induction of Breg cells by lactic acid: a direct pathway that enhances the CD40 signal in B cells, and an indirect pathway that affects B cells by activating the exchange protein directly activated by cAMP (EPAC) 1/2 in non-B cells. In tumor-bearing mice, the levels of H3K27ac of tumor-infiltrating B cells were significantly higher than splenic B cells and were suppressed by intraperitoneal injection of the EPAC1/2 inhibitor. In conclusion, tumor-derived lactic acid increases H3K27ac and IL-10-producing Breg cells, causing the suppression of anti-tumor immunity., (© 2024 UICC.)

Aims: Gestational diabetes mellitus (GDM) provides offspring with a hyper-metabolic intrauterine microenvironment. In this study, we aimed to identify key differential microRNAs in GDM-derived exosomes and explore the potential mechanisms of abnormal embryonic development of islets in offspring., Main Methods: Exosomes were extracted from umbilical vein blood of GDM and non-GDM (NGDM) parturients for microRNA sequencing. Offspring islets were collected on E18.5 and P0 to detect the expression and location of key proteins by immunofluorescence. Target binding of miR-7-19488 and PIK3R2 mRNA was verified using a dual-luciferase reporter assay. The miR-7-19488-mimic, PI3K/mTOR inhibitors were used to treat primarily islet cells to explore the relationship among miR-7-19488, PI3K, and Akt-FoxO1/mTORC1 signaling. The miR-7-19488 agomir was synthesized for further in vivo validation., Key Findings: GDM-derived exosomes caused the overdevelopment of offspring-islets at E18.5 with an increased production of insulin and glucagon co-staining cells, increased number of α cells synthesizing GLP-1, and stimulation of mTORC1 singling, which were more serious at birth. The up-regulated miR-7-19488 in GDM-exosomes targeted PIK3R2 mRNA, leading to translation stagnation of p85β and activation of PI3K-Akt singling in fetal islets. Importantly, the activated PI3K-Akt-FoxO1 singling promoted development and differentiation of α and β cells and enhanced the GLP-1/GLP-1R axis, which cooperates with miR-7-19488 to activate PI3K-Akt-FoxO1/mTORC1 signaling, leading to the early initiation of the functional maturation of overdeveloped β cells., Significance: miR-7-19488 loaded in GDM-derived exosomes induce the abnormal overdevelopment and functional maturation of fetal islets, which is one of the contributors of high incidence of diabetes in adulthood., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2025. Published by Elsevier Inc.)

Aims: Gut dysbiosis modulates CNS complications and cognitive decline through the gut-brain axis. The study aims to investigate the molecular mechanisms involved in gut dysbiosis-associated cognitive changes and the potential effects of probiotics in high fat-high carbohydrate diet-induced gut dysbiosis-associated neurodegeneration., Materials and Methods: We used high fat, high-carbohydrate diet (HFHCD) and high-fat diet (HFD) to induce gut dysbiosis-associated neurodegeneration in C57BL/6 mice. IVIS imaging system and biochemical changes using ELISA measured intestinal inflammation. We used fecal samples for qPCR profiling of intestinal bacteria, and serum was used for inflammatory marker analysis using ELISA. Behavioral studies measured cognitive changes, while histopathology, immunohistochemistry, and western blot analysis of hippocampal samples measured protein changes., Key Findings: The behavioral studies showed a significant decrease in cognitive function associated with gut dysbiosis in HFHCD and HFD animals. Gut dysbiosis was associated with intestinal inflammation and increased intestinal permeability, followed by systemic and neuroinflammatory changes. Molecular signaling studies showed the involvement of AIM2 inflammasome and cGAS-STING signaling pathways in neurodegeneration for HFHCD animals. Administration of probiotics restored the above processes and prevented gut dysbiosis-associated memory decline in mice., Significance: The study shows that alteration in microbial composition due to prolonged HFHCD could contribute to intestinal inflammation and increased intestinal permeability, facilitating the translocation of microbial toxins like LPS, leading to systemic inflammation, which eventually leads to neuroinflammation and neurodegeneration., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest for the data presented in the manuscript titled “Role of AIM2 and cGAS-STING Signalling in High Fat High Carbohydrate Diet Induced Gut Dysbiosis Associated Cognitive decline”., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Ginkgolides are secondary metabolites unique to Ginkgo biloba with the potential to prevent and treat cardiovascular and cerebrovascular diseases. Although the biosynthetic pathways of ginkgolides have been partly uncovered, the mechanism regulating their biosynthesis is still largely unknown. Here, using multiomic and genetic analyses, we report the identification of a transcription factor, named ETHYLENE RESPONSE FACTOR ASSOCIATED WITH GINKGOLIDE BIOSYNTHESIS (GbEAG), as a critical regulator of ginkgolide biosynthesis. GbEAG is highly expressed in the roots of G. biloba, and its expression is significantly induced by methyl jasmonate (MeJA). Ginkgolide content was significantly increased in roots by overexpressing GbEAG using a "cut-dip-regeneration" system. GbEAG positively regulates ginkgolide biosynthesis by directly binding to the GCC-boxes in the promoter regions of genes involved in the biosynthesis of ginkgolides, such as ISOPENTENYL DIPHOSPHATE ISOMERASE ( GbIDI ) and CYTOCHROME P450 7005C3 ( GbCYP7005C3 ). GbEAG mediates the jasmonic acid (JA)-activated ginkgolide synthesis through its direct interaction with the JASMONATE ZINC-FINGER INFLORESCENCE MERISTEM DOMAIN 3 (GbJAZ3) repressor. Importantly, we also found that the central light-response regulator ELONGATED HYPOCOTYL 5 (GbHY5) mediates light induction of ginkgolide biosynthesis by binding to the G-box in the GbEAG promoter. Our findings provide mechanistic insights into the coordinated regulation of ginkgolide biosynthesis via JA and light signals, with GbEAG as a central regulator in G. biloba, and shed light on the potential to develop ginkgolide-rich varieties through molecular breeding and gene editing., Competing Interests: Competing interests statement:The authors declare no competing interest.

Tumor progression is suppressed by inherent cellular mechanisms such as apoptosis. The p53 tumor suppressor gene is the most commonly mutated gene in human cancer and plays a pivotal role in tumor suppression. RPRM is a target gene of p53 known to be involved in tumor suppression, but its molecular function has remained elusive. Here, we report that Reprimo (the protein product of RPRM ) is secreted and extrinsically induces apoptosis in recipient cells. We identified FAT1, FAT4, CELSR1, CELSR2, and CELSR3, members of the protocadherin family, as receptors for Reprimo. Subsequent analyses revealed that Reprimo acts upstream of the Hippo-YAP/TAZ-p73 axis and induces apoptosis by transactivating various proapoptotic genes. In vivo analyses further support the tumor-suppressive effects of secreted Reprimo. These findings identify the p53-Reprimo-Hippo-YAP/TAZ-p73 axis as an extrinsic apoptosis pathway that plays a crucial role in tumor suppression. Our finding of the innate tumor eliminator Reprimo and the downstream pathway offers a promising avenue for the pharmacological treatment of cancer., Competing Interests: Competing interests statement:The authors declare no competing interest.

Inhibiting the androgen receptor (AR) is effective for treatment of advanced prostate cancers because of their AR-dependent luminal epithelial cell identity. Tumors progress during therapy to castration-resistant prostate cancer (CRPC) by restoring AR signaling and maintaining luminal identity or by converting through lineage plasticity to a neuroendocrine (NE) identity or double-negative CRPC (DNPC) lacking luminal or NE identities. Here, we show that DNPC cells express genes defining basal, club, and hillock epithelial cells from benign prostate. We identified KLF5 as a regulator of genes defining this mixed basal, club, and hillock cell identity in DNPC models. KLF5-mediated upregulation of RARG uncovered a DNPC sensitivity to growth inhibition by retinoic acid receptor agonists, which down-regulated KLF5 and up-regulated AR. These findings offer CRPC classifications based on prostate epithelial cell identities and nominate KLF5 and RARG as therapeutic targets for CRPC displaying a mixed basal, club, and hillock identity., Competing Interests: Competing interests statement:S.M.D. has served as principal investigator on grants to University of Minnesota from Astellas/Pfizer and Janssen. S.M.D. has served as advisor/consultant for Celgene/Bristol Myers Squibb, Janssen, and Oncternal Therapeutics. P.S.N. has served as a paid advisor to Bristol Myers Squibb, Janssen, Pfizer and received research funding from Janssen for work unrelated to the present study. E.C. served as a paid consultant to DotQuant, and received Institutional sponsored research funding unrelated to this work from Astra Zeneca, AbbVie, Gilead, Sanofi, Zenith Epigenetics, Bayer Pharmaceuticals, Forma Therapeutics, Genentech, GSK, Janssen Research, Kronos Bio, Foghorn Therapeutics, K36, and MacroGenics. W.D. is a recipient of the Emmanuel van der Schueren scholarship of “Kom Op Tegen Kanker.” S.J. is a Senior Clinical Investigator of the FWO. F.C. and S.J. were funded by KU Leuven grant nr C14/19/100. H.E.B. is a co-founder of EMRGNSE LLC. E.S.A. reports grants and personal fees from Janssen, Sanofi, Bayer, Bristol Myers Squibb, Curium, Merck, Pfizer, AstraZeneca, Clovis, and Constellation; personal fees from Astellas, Amgen, Blue Earth, Exact Sciences, Invitae, Eli Lilly, and Foundation Medicine; and grants from Novartis, Celgene, and Orion outside the submitted work. E.S.A. has a patent for an AR-V7 biomarker technology issued and licensed to Qiagen.

Soil salinity presents a dual challenge for plants, involving both osmotic and ionic stress. In response, plants deploy distinct yet interconnected mechanisms to cope with these facets of salinity stress. In this investigation, we observed a substantial overlap in the salt (NaCl)-induced transcriptional responses of Arabidopsis roots with those triggered by osmotic stress or the plant stress hormone abscisic acid (ABA), as anticipated. Notably, a specific cluster of genes responded uniquely to sodium (Na + ) ions and are not regulated by the known monovalent cation sensing mechanism MOCA1 . Surprisingly, expression of sodium-induced genes exhibited a negative correlation with the ABA response and preceded the activation of genes induced by the osmotic stress component of salt. Elevated exogenous ABA levels resulted in the complete abolition of sodium-induced responses. Consistently, the ABA insensitive snrk2.2/2.3 double mutant displayed prolonged sodium-induced gene expression, coupled with increased root cell damage and root swelling under high salinity conditions. Moreover, ABA biosynthesis and signaling mutants were unable to redirect root growth to avoid high sodium concentrations and had increased sodium accumulation in the shoot. In summary, our findings unveil an unexpected and pivotal role for ABA signaling in mitigating cellular damage induced by salinity stress and modulating sodium-induced responses in plant roots., Competing Interests: Competing interests statement:The authors declare no competing interest.

Abstract: Patients with cytotoxic T-lymphocyte-associated protein 4 (CTLA4) deficiency exhibit profound humoral immune dysfunction, yet the basis for the B-cell defect is not known. We observed a marked reduction in transitional-to-follicular (FO) B-cell development in patients with CTLA4 deficiency, correlating with decreased CTLA4 function in regulatory T cells, increased CD40L levels in effector CD4+ T cells, and increased mammalian target of rapamycin complex 1 (mTORC1) signaling in transitional B cells (TrBs). Treatment of TrBs with CD40L was sufficient to induce mTORC1 signaling and inhibit FO B-cell maturation in vitro. Frequent cell-to-cell contacts between CD40L+ T cells and immunoglobulin D-positive CD27- B cells were observed in patient lymph nodes. FO B-cell maturation in patients with CTLA4 deficiency was partially rescued after CTLA4 replacement therapy in vivo. We conclude that functional regulatory T cells and the containment of excessive T-cell activation may be required for human TrBs to mature and attain metabolic quiescence at the FO B-cell stage., (© 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Pyruvate Kinase Muscle Isozyme (PKM), as a member of the pyruvate kinase, is a key enzyme in glycolysis. Numerous tumors have demonstrated its oncogenic properties. There is, however, no pan-carcinogenic analysis for PKM., Methods: A thorough analysis of PKM across various types of cancer was carried out using bioinformatics resources like The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) database. This study involved analyzing the role of PKM in 33 various types of cancers, along with investigating gene expressions, survival rates, clinical importance, genetic changes, immune system presence, and related signaling pathways. Furthermore, we evaluated the effects of PKM knockdown on human colon carcinoma, and glioblastoma cell lines by in vitro experimentation., Results: In most tumors, PKM expression was markedly increased and was associated with unfavorable overall survival (OS) in certain individuals. In addition, infiltration of macrophages was associated with PKM expression in various tumors. PKM was linked to glycolysis/gluconeogenesis, HIF-1 signaling, carbon metabolism, and NADPH regeneration in a mechanistic manner. Additionally, cell experiments showed that the knockdown of PKM could reduce the proliferation and migration abilities while promoting the apoptosis of Caco-2, and U-87 MG cells., Conclusion: PKM controls immune cell infiltration, impacts patient outcomes in various types of cancer, and plays an essential role in proliferation and migration in some tumor cells by affecting glycometabolism. The PKM molecule may serve as a potential prognostic biomarker and therapeutic target for human cancers., 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.)

Glutaminyl-peptide cyclotransferase-like protein (QPCTL) is a newly discovered enzyme that has sparked interest owing to its possible role in cancer genesis and progression. Initially discovered as a post-translational modification regulator of protein maturation, QPCTL has emerged as a key participant in cancer biology. Recent research has linked QPCTL to numerous essential cancer-related processes, including cell proliferation, migration, invasion, and apoptosis. Furthermore, QPCTL expression changes have been seen in a variety of cancer types, underlining its potential as a diagnostic and prognostic marker. The molecular mechanisms behind QPCTL's participation in cancer will be examined in this review. We investigate its involvement in the control of signaling pathways and the modification of cellular activities that are important in cancer. We also examine the clinical importance of QPCTL, including as its relationship with tumor development, metastasis, and response to treatment. We also discuss the possible therapeutic implications of targeting QPCTL in cancer therapy. QPCTL is a prospective target for the development of innovative anticancer treatments due to its participation in several cancer-associated 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 © 2024 Elsevier B.V. All rights reserved.)

Unravelling the intricate patterns of site-specific protein phosphorylation during Epimorphic regeneration holds the key to unlocking the secrets of tissue complexity. Understanding these precise modifications and their impact on protein function could shed light on the remarkable regenerative capacity of tissues, with potential implications for therapeutic interventions. In this study we have systematically mapped the global phosphorylation modifications within regenerating tissue of zebrafish caudal fins, elucidating the intricate landscape of signalling pathway associate with the regeneration process. Based on mass spectrometry analysis, we identified 440 phosphorylated proteins using the immunoprecipitation method with phosphoserine, phosphothreonine, and phosphotyrosine antibodies, and 74 phosphorylated proteins using the TiO₂ column enrichment method were found differentially phosphorylated during the regeneration process from 12 hpa to 7 dpa compared to the control. Interestingly 95% of the proteins identified from TiO 2 enrichment method were also found to be identified through the phosphoprotein antibody pull down method impacting the high accuracy and significance of the methods and greater association of the 70 proteins undergoing differential phosphorylation during the process of regeneration. Whole mount immunohistochemistry analysis reveals high association of phosphorylation at 1dpa, 2dpa and 3dpa regeneration time points. Network pathway analysis revealed that cancer-related diseases, organismal injuries and abnormalities as the most strongly associated canonical network pathways with the differentially expressed phosphoproteome in the mechanism of regeneration. This research enhances our comprehension on protein post-translational modification in the context of zebrafish caudal fin tissue regeneration, shedding light on its prospective application in the field of regenerative medicine., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval: The experimental protocol was approved by Centre for Cellular and Molecular Biology institutional animal ethics committee (IAEC/CCMB/Protocol #50/2013)., (© 2025. The Author(s).)

Hepatocellular carcinoma is considered to be the fifth most rampant type of cancer in the whole world and has a high death rate. The hypoxic microenvironment is one of the typical features of tumor tissues and has an important impact on the activity of multiple signaling pathways. It is of great significance to study the effects of hypoxia on the pathophysiological processes and molecular mechanisms of HCC. Signalling pathways associated with SHP2 were analysed using bioinformatics. Detection of relevant protein expression using Western blotting. Tube formation assay was used in evalution of the angiogenic potential. The concentrations of MDA and SOD were measured by ELISA. The cell migration and invasion ability were measured with a scratch wound assay and transwell assay in SMMC-7721, HepG2 and Huh-7 cells. The effect of hypoxia on the growth of hepatocellular carcinoma was examined using subcutaneous graft tumors and HE staining experiments in nude mice. Bioinformatics analysis of SHP2 negatively correlates with the PI3K signalling pathway. Hypoxia promotes the concentration of MDA and inhibited the concentration of SOD. Hypoxia may up-regulate NOX2, NOX4 and p-PI3K and down-regulate the treatment of p-SHP2. Compared with NC group, the expression of SHP2 and p-SHP2 was inhibited in SHP2 KD group and the expression of p-PI3K, HIF1α, COX2, FOXM1, β-catenin and MMP9 was promoted. However, the differences of the expression of p-PI3K, HIF1α, COX2, FOXM1, β-catenin and MMP9 between the two groups were abolished after the addition of PI3K inhibitor. The angiogenesis, migration and invasion abilities were significantly increased in SHP2 KD group compared with NC group. Similarly, after the addition of PI3K inhibitor, the difference of these abilities between the two groups was eliminated. Hypoxia can promote the growth of hepatocellular carcinoma. Hypoxia can activate the oxidative stress-mediated SHP2/PI3K signaling pathway to promote angiogenesis, migration, and invasion in hepatocellular carcinoma, thus advancing the development of hepatocellular carcinoma., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: All animal protocols were approved by the Animal Care and Use Committee of the Fourth Hospital of Hebei Medical University (Ethical Number: No.2023KS241)., (© 2025. The Author(s).)

Wounds that represent one of the most critical complications can occur in individuals suffering from diabetes mellitus, and results in the need for hospitalisation and, in severe cases, require amputation. This condition is primarily characterized by infections, persistent inflammation, and delayed healing processes, which exacerbate the overall health of the patients. As per the standard mechanism, signalling pathways such as PI3K/AKT, HIF-1, TGF-β, Notch, Wnt/β-Cat, NF-κB, JAK/STAT, TLR, and Nrf2 play major roles in inflammatory, proliferative and remodelling phases of wound healing. However, dysregulation of the above pathways has been seen during the healing of diabetic wounds. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate the expression of various genes and signalling pathways which are associated with the process of wound healing. In the past few years, there has been a great deal of interest in the potential of miRNAs as biological agents in the management of a number of disorders. These miRNAs have been shown to modulate expression of genes involved in the healing process of wounds. There have been previous reviews pertaining to clinical trials examining miRNAs in several disorders, but only a few clinical studies have examined involvement of miRNAs in healing of wounds. Considering the therapeutic promise, there are several obstacles concerning their instabilities and inefficient delivery into the target cells. Therefore, this review is an attempt to discuss precise roles of signalling pathways and miRNAs in different phases of wound healing, and their aberrant regulation in diabetic wounds, particularly. It has also compiled a range of delivery mechanisms as well as an overview of the latest findings pertaining to miRNAs and associated delivery systems for improved healing of diabetic wounds., 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.)

Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease, characterized by inadequate alveolar regeneration and ectopic bronchiolization. While some molecular pathways regulating lung progenitor cells have been described, the role of metabolic pathways in alveolar regeneration is poorly understood. We report that expression of fatty acid oxidation (FAO) genes is significantly diminished in alveolar epithelial cells of IPF lungs by single-cell RNA sequencing and tissue staining. Genetic and pharmacological inhibition in AT2 cells of carnitine palmitoyltransferase 1a (CPT1a), the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition of aberrant intermediate states expressing basaloid, and airway secretory cell markers SCGB1A1 and SCGB3A2. Furthermore, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing lung fibrosis with an accumulation of epithelial cells expressing markers of intermediate cells, airway secretory cells, and senescence. We found that deficiency of CPT1a causes a decrease in SMAD7 protein levels and TGF-β signaling pathway activation. These findings suggest that the mitochondrial FAO metabolic pathway contributes to the regulation of lung progenitor cell repair responses and deficiency of FAO contributes to aberrant lung repair and the development of lung fibrosis.

Strictures in inflammatory bowel disease, especially Crohn's disease (CD), are characterized by increased intestinal wall thickness, which, according to recent accumulating data, is mainly attributed to the expansion of the intestinal smooth muscle layers and to a lesser extent to collagen deposition. In this review, we will discuss the role of intestinal smooth muscle cells (SMCs) as crucial orchestrators of stricture formation. Activated SMCs can synthesize extracellular matrix (ECM), thus contributing to intestinal fibrosis, as well as growth factors and cytokines that can further enhance ECM production, stimulate other surrounding mesenchymal and immune cells, and increase SMC proliferation via paracrine or autocrine signaling. There is also evidence that, in stricturing CD, a phenotypic modulation of SMC toward a myofibroblast-like synthetic phenotype takes place. Moreover, the molecular mechanisms and signaling pathways that regulate SMC hyperplasia/hypertrophy will be extensively reviewed. The understanding of the cellular network and the molecular background behind stricture formation is essential for the design of effective anti-fibrotic strategies, and SMCs might be a promising therapeutic target in the future., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. 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.)

It has been challenging to determine how a ligand that binds to a receptor activates downstream signaling pathways and to predict the strength of signaling. The challenge is compounded by functional selectivity, in which a single ligand binding to a single receptor can activate multiple signaling pathways at different levels. Spectroscopic studies show that in the largest class of cell surface receptors, 7 transmembrane receptors (7TMRs), activation is associated with ligand-induced shifts in the equilibria of intracellular pocket conformations in the absence of transducer proteins. We hypothesized that signaling through the μ opioid receptor, a prototypical 7TMR, is linearly proportional to the equilibrium probability of observing intracellular pocket conformations in the receptor-ligand complex. Here, we show that a machine learning model based on this hypothesis accurately calculates the efficacy of both G protein and β-arrestin-2 signaling. Structural features that the model associates with activation are intracellular pocket expansion, toggle switch rotation, and sodium binding pocket collapse. Distinct pathways are activated by different arrangements of the ligand and sodium binding pockets and the intracellular pocket. While recent work has categorized ligands as active or inactive (or partially active) based on binding affinities to two conformations, our approach accurately computes signaling efficacy along multiple pathways.

Main Conclusion: Phosphorylation of PBL19 mediated by CERK1 in response to chitin is crucial for enhancing plant defense against fungal pathogens, underscoring the importance of chitin signaling in plant immune responses. Fungal pathogens pose a serious threat to global agriculture, causing substantial yield losses. Plants have evolved complex defense mechanisms, including the recognition of chitin, a major component of fungal cell walls, to activate immune responses that are crucial for defense against pathogens. Protein phosphorylation plays a pivotal role in regulating these responses, fine-tuning immune signaling pathways. Here, we investigate PBL19, a member of the RLCK VII subfamily in Arabidopsis thaliana, known for its pivotal role in chitin signaling pathways. Our study reveals that upon chitin perception, PBL19 undergoes phosphorylation-mediated by the receptor CERK1. Through mass spectrometry analysis, we identified eight specific phosphorylation sites on PBL19. Functional characterization revealed their crucial role in enhancing fungal resistance mechanisms in plants. This study advances our understanding of how plants employ phosphorylation-mediated signaling to combat fungal pathogens, providing insights into fundamental mechanisms of plant immunity., Competing Interests: Declarations. Conflict of interest: Authors declare that they do not have any conflict of interest., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diabetes mellitus (DM) and osteoporosis (OP) co-morbidity (DMOP) pose major health challenges owing to their complex pathophysiological interactions. The aim of this study was to identify and validate key genes implicated in the pathogenesis of both conditions. By employing the Mfuzz time-series gene clustering method combined with transcriptome sequencing of patient serum, we systematically delineated gene expression patterns during the transition from a healthy state through DM to DMOP. These findings were further validated using external datasets, and a series of functional enrichment analyses, gene set enrichment analyses, and immune cell infiltration studies were conducted. Our analyses revealed a distinct progression pattern from a normal state through DM to DMOP, characterized by dynamic gene expression changes. Notably, PRKD2 emerged as a significantly downregulated gene in DMOP, highlighting its crucial role in disease pathogenesis. Further analyses revealed the involvement of PRKD2 in key signaling pathways, especially the Wnt and IL-18 pathways, which are critical for bone and glucose metabolism. Validation in cellular and animal models confirmed the role of PRKD2 in apoptosis and bone metabolism, emphasizing its therapeutic potential. In conclusion, our findings establish PRKD2 as a pivotal molecule in DMOP, offering fresh insights into its mechanisms and affirming its value as a therapeutic target., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval: This study was designed and conducted to uphold the highest ethical standards for research involving both human participants and animals. In alignment with the ethical principles outlined in the 1964 Declaration of Helsinki and its subsequent amendments, we obtained ethical approval for our research involving human participants from the Institutional Review Board (IRB) of Lanzhou University Second Hospital, formally known as the Ethics Committee of Lanzhou University Second Hospital, under the approval number 2024 A-692. For research involving animals, we strictly adhered to the guidelines set forth by the Institutional Animal Care and Use Committee (IACUC) of Lanzhou University Second Hospital, formally known as the Animal Ethics Committee of Lanzhou University Second Hospital, which approved our experimental protocols under the approval number D2024-632. We took utmost care to ensure animal welfare throughout the study. Animals were anesthetized and euthanized using intraperitoneal injections of pentobarbital, with dosages calculated based on body weight to guarantee a rapid and painless procedure. All experimental protocols involving human participants were approved by the IRB of Lanzhou University Second Hospital. All procedures involving animals were performed in strict compliance with the guidelines established by the IACUC of Lanzhou University Second Hospital, formally known as the Animal Ethics Committee, and received approval. This study strictly adhered to the guidelines set forth by the “Animal Research: Reporting of In Vivo Experiments” (ARRIVE guidelines) for the reporting of standards and transparency in laboratory animal research ( https://arriveguidelines.org ). Consent to participate: Informed consent was obtained from all individual participants included in the study., (© 2025. The Author(s).)

Previous research has identified a variety of factors that contribute to the development and maintenance of wounds. Concurrently, electroacupuncture has been demonstrated to facilitate wound healing. However, the effects of transcutaneous electrical acustimulation (TEA) on wound healing, as well as its relationship with key factors such as Wnt3a, TGF-β, Akt, c-Myc, VEGF-A, SP1, nitric oxide (NO), and mitochondrial function, remain largely unexplored. We hypothesize that TEA will activate the signaling factors and enhance mitochondrial functions to promote the repair of skin wounds in mice. An in vivo experimental study was conducted utilizing mouse models with skin wounds. The study comprised three groups: a TEA treatment with wound group, a skin wound model group, and a control group. Wound areas were measured by calculating the product of the length and width of each wound using calipers. Single-cell suspensions were prepared by excising the wound and the immediately surrounding tissue. These suspensions were stained with Trypan blue to assess cell viability, with specific probes to measure the rate of reactive oxygen species (ROS) positivity, and with reagents to quantify NO content. Western blotting (WB) was employed to evaluate protein levels associated with tissue changes, while quantitative polymerase chain reaction (qPCR) was used to assess RNA expression levels. Immunofluorescence staining was performed to visualize protein content and other relevant cellular structures within tissue sections. TEA exhibited anti-inflammatory properties and promoted wound healing in mice. Western blot analysis revealed that TEA enhanced the expression of proteins associated with Wnt3a, TGF-β, Akt, c-Myc, VEGF-A, and SP1 during the wound healing process. Immunofluorescence staining of tissue sections indicated that TEA upregulated the expression of COL1A1, MFN1, GRP75, GRP78, GRP75/ROS, GRP78/ROS, ISCU, and UCP1 while downregulating FIS1. Additionally, qPCR results demonstrated that TEA promoted the expression of IL-10 and miRNA205-5p while inhibiting MMP9 levels. TEA modulates various signaling molecules, influences chaperone proteins related to stress recovery responses, along with mitochondrial dynamics and metabolism., Competing Interests: Declarations. Conflict of interest: The authors confirm that there are no conflicts of interest. Ethical approval and consent to participate: The study has been approved with the numbers of AN-STA-00000095 by animal ethic committee of City University of Hong Kong. Consent for publication: All author consent for publication., (© 2025. The Author(s).)

Bladder cancer (BLCA) is one of the ten most common cancers worldwide. However, the deregulation of PROS1 and its specific function in BLCA is not well understood. By combining proteomic and transcriptomic datasets, we discovered PROS1 expression was significantly reduced in BLCA tissues and revealed the clinical relevance of PROS1 with BLCA. Analysis of multiple BLCA datasets consistently showed the group with reduced PROS1 expression was linked to cancer-promoting pathways, more aggressive characteristics, and a greater chance of responding positively to immunotherapy. Next, various functional experiments were performed and the results revealed PROS1 overexpression inhibited the proliferation, cell cycle progression, migration, invasion, and angiogenesis of BLCA. In recovery trials, the AKT activator SC79 offered additional proof that PROS1 may influence BLCA cells via the AKT/GSK3β/β-catenin pathway. In conclusion, as an angiogenesis-related gene, PROS1 may play an inhibitory role in the biological functions of bladder cancer., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: We confirmed that all experiments in this study were performed in accordance with the relevant guidelines and regulations. All the procedure of the study is followed by the ARRIVE guidelines., (© 2025. The Author(s).)

Background: Diabetic foot ulcers (DFUs) represent a major complication of diabetes, often leading to poor healing outcomes with conventional treatments. Mesenchymal stem cell (MSC) therapies have emerged as a promising alternative, given their potential to modulate various pathways involved in wound healing. This study evaluates and compares the therapeutic potential of MSCs derived from perinatal tissues-human umbilical cord MSCs (hUCMSCs), human chorionic villi MSCs (hCVMSCs), and human decidua basalis MSCs (hDCMSCs)-in a diabetic wound healing model., Methods: We performed in vitro and in vivo studies to compare the efficacy of hUCMSCs, hCVMSCs, and hDCMSCs. Mass spectrometry was used to analyze the secreted proteins of the MSCs. We incorporated the MSCs into a polyethylene glycol diacrylate (PEGDA) and sodium alginate (SA) hydrogel matrix with collagen I (Col-I) to evaluate their effects on wound healing., Results: All three types of MSCs promoted wound healing, with hUCMSCs and hCVMSCs showing stronger effects compared to hDCMSCs. Both hUCMSCs and hCVMSCs demonstrated robust wound healing kinetics, with enhanced keratinocyte proliferation (KRT14 + /Ki67 + cells), maturation (KRT10/KRT14 ratio), and angiogenesis. In vitro studies demonstrated that the MSC-derived secretome enhanced keratinocyte proliferation and migration, endothelial cell function and stem cell recruitment, indicating robust paracrine effects. Mass spectrometry revealed a conserved set of proteins including THBS1 (thrombospondin 1), SERPINE1 (serpin family E member 1), ANXA1 (annexin A1), LOX (lysyl oxidase), and ITGB1 (integrin beta-1) which are involved in extracellular matrix (ECM) organization and wound healing, with the PI3K/AKT signaling pathway playing a central role. The PEGDA/SA/Col-I hydrogel demonstrated a unique balance of mechanical and biological properties and an optimal environment for MSC viability and function. Application of either hUCMSC- or hCVMSC-laden hydrogels resulted in accelerated wound closure, improved re-epithelialization, increased collagen deposition, and enhanced vascularization in vivo., Conclusions: MSCs From perinatal tissues particularly hUCMSCs and hCVMSCs significantly enhance diabetic wound healing through PI3K/AKT pathway activation while hDCMSCs exhibited weaker efficacy. The PEGDA/SA/Col-I hydrogel supports MSC viability and function offering a promising scaffold for DFU treatment. These findings underscore the potential of specific perinatal MSCs and optimized hydrogel formulations in advancing diabetic wound care., Competing Interests: Declarations. Ethics approval and consent to participate: Isolation of human umbilical cord- and placenta-derived MSCs was approved by the Joint CUHK-NTEC Clinical Research Ethics Committee (Title: Placenta derived genes analysis in placenta and maternal circulation in singleton pregnancies complicated with fetal growth restriction; Ref: 2020.313; Year of approval: 2020). The use of human bone marrow for MSC isolation was approved by Joint CUHK-NTEC Clinical Research Ethics Committee (Title: A novel preclinical treatment strategy for enhancing chemosensitivity of pediatric B-precursor acute lymphoblastic leukemia by disruption of leukemia-stroma interaction using CD9-neutralizing antibody in a mouse model; Ref: 2015.018; Year of approval: 2015). Written informed consent for participation in the study or the use of samples was provided to the patients or their guardians. All animal use and research protocols in this study were approved by the Laboratory Animal Experimentation Ethical Committee, Chinese University of Hong Kong (Title: Development of stem cell-based therapy for diabetic foot ulcer (DFU); Ref: 21–162-MIS; Year of approval: 2021) and were in accordance with the Guideline for the Care and Use of Laboratory Animals. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2025. The Author(s).)

In living organisms, cells synergistically couple cascade reaction pathways to achieve inter- and intracellular signal transduction by transmembrane protein receptors. The construction and assembly of synthetic receptor analogs that can mimic such biological processes is a central goal of synthetic biochemistry and bionanotechnology to endow receptors with user-defined signal transduction effects. However, designing artificial transmembrane receptors with the desired input, output, and performance parameters are challenging. Here we show that the dimerization of synthetic transmembrane DNA receptors executes a systematically engineered sensing and actuation cascade in response to external molecular signals. The synthetic DNA receptors are composed of three parts, including an extracellular signal reception part, a lipophilic transmembrane anchoring part, and an intracellular signal output part. Upon the input of external signals, the DNA receptors can form dimers on the cell surface triggered by configuration changes, leading to a series of downstream cascade events including communication between donor and recipient cells, gene transcription regulation, protein level control, and cell apoptosis. We believe this work establishes a flexible cell surface engineering strategy that is broadly applicable to implement sophisticated biological functions., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Hepatic stellate cells (HSCs) transdifferentiate into myofibroblasts during liver fibrosis and exhibit increased glycolysis. Phosphorylated focal adhesion kinase (FAK) (pY397-FAK) promotes monocarboxylate transporter 1 (MCT-1) expression in HSCs to increase aerobic glycolysis and cause liver fibrosis. A combined multiomics analysis of C57BL/6 mice with tetrachloromethane (CCl 4 )-induced liver fibrosis was performed to identify the downstream FAK signaling pathway. The effect of the FAK inhibitor PF562271 on CCl 4 -induced liver fibrosis was explored by immunofluorescence of liver tissues. The migration, proliferation and aerobic glycolysis of LX-2 cells after stimulation and activation by transforming growth factor beta-1 (TGF-β1) or suppression by PF562271 was assessed in vitro. Multiomics analysis of a successfully generated CCl4-induced liver fibrosis mouse model was performed. FAK and cyclin D1 were significantly enriched in mice with CCl4-induced liver fibrosis. In vivo, the MCT-1 and alpha smooth muscle actin (α-SMA) levels were increased in mice with CCl4-induced liver fibrosis, and MCT-1 and α-SMA expression decreased after PF562271 treatment. In vitro, PF562271 alleviated TGF-β1-induced LX-2 activation. LX-2 cells showed diminished migration, proliferation, and aerobic glycolysis after PF562271 intervention. FAK promotes aerobic glycolysis in LX-2 cells through the cyclin D1/c-Myc/MCT-1 pathway, thereby increasing liver fibrosis., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Institutional Review Board statement: This study was reviewed and approved by the Institutional Review Board of the Affiliated Hospital of Guizhou Medical University (Approval 2018 Ethics Review No. 032). Institutional animal care and use committee statement: Animal care and experimental procedures were authorized by the Animal Ethics Committee of Guizhou Medical University (No. 1801109)., (© 2025. The Author(s).)

Epithelial homeostasis ensures that the epithelium can perform its normal physiological functions. Mechanical signaling response through integrin-mediated adhesions of the basement membrane (BM) is crucial for maintaining epithelial homeostasis. The essential mechanosensors YAP and the paralog TAZ (YAP/TAZ) have been shown to play a critical role in epithelial homeostasis, but the key regulator that mediates mechanical signaling to YAP/TAZ in maintaining epithelial homeostasis has not been fully understood. In this study, we noticed that mechanical signals correlated with YAP/TAZ activation and basal state maintenance in epithelial stem/progenitor cells through immunohistochemistry. Subsequently, we found that inhibition of focal adhesion kinase (FAK) suppressed YAP/TAZ activation in the human keratinocyte line HaCaT cells. Furthermore, inhibition of the interaction between YAP/TAZ and the transcriptional enhanced associate domains (TEADs) resulted in the differentiation of HaCaT cells. Finally, we used primary mouse epithelial cells to reconstruct the epithelium in vitro and found that FAK inhibition led to both a reduction in YAP/TAZ activity and an increase of differentiation in the basal layer cells. In conclusion, our findings reveal that FAK mediates mechanical signaling to maintain epithelial homeostasis via YAP/TAZ-TEADs., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Myopia has become a worldwide public health problem. In this study, we constructed a form deprivation (FD) myopia mouse model and explored the potential role of NF-κB pathway and inflammatory cytokines in scleral remodeling during myopia development. Wild-type (WT) mice and C6-knockout (KO) mice were categorized into two groups: FD and normal control (NC). The right eye was covered using a translucent balloon for 4 weeks, and the left eye remained untreated which served as self-control. NC group received no treatment. Refractive error and axial length were measured at baseline, 2 weeks, 4 weeks later under normal visual conditions, and 4 weeks after FD. The mRNA and protein levels of scleral TNF-α, IL-6, IL-1β, MMP-2, collagen I, and p-NF-κB p65 were detected using quantitative PCR and western blot. Under normal visual conditions, no significant difference existed in refraction and axial length between WT and C6 KO mice. After 4 weeks of deprivation, the interocular differences of C6 KO mice were lower than those of WT mice (refraction - 2.41 ± 0.86D vs. - 4.33 ± 0.87D, P = 0.003; axial length 0.044 ± 0.028 mm vs. 0.082 ± 0.026 mm, P = 0.034). Moreover, TNF-α, IL-6, IL-1β, MMP-2, and p-NF-κB p65 levels increased, and collagen I levels decreased in deprived eyes of WT mice. Whereas these trends were weakened in C6 KO mice. Scleral C5b-9 could activate the NF-κB pathway, promoting the expression of inflammatory cytokines and MMP-2 levels, which ultimately affected scleral remodeling., Competing Interests: Declarations. Ethics approval and consent to participate: All animal procedures were approved by the Institutional Review Board of Peking Union Medical College Hospital. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Trichome initiation and development is regulated by a diverse range of environmental signals. However, how leaf carbohydrate status determines the trichome initiation and development of systemic developing leaves remains unclear. Here, we found that a specific organ (such as a mature leaf) could function as a nutrient sensor, subsequently promoting or suppressing nonautonomous regulation of trichome initiation and development in response to alternations in nutrient levels. This physical phenomenon was regulated by a sucrose ⟶ ACS7 ⟶ ethylene ⟶ EIN3 ⟶ SUC4 ⟶ sucrose pathway in mature leaves, with a remote control of trichome production in newly developing leaves via a sucrose ⟶ ACS7 ⟶ ethylene ⟶ EIN3 ⟶ TTG1 pathway. These data provide insights into how mature leaves function as nutrient sensors that control trichome formation within distant developing leaves through a nutrient sensor-relay mechanism. Our findings uncover both a previously unidentified, nutrient sensing-regulatory mechanism and the cognate underpinning molecular architecture.

Exogenous light cues and the phytohormone abscisic acid (ABA) regulate several aspects of plant growth and development. In recent years, the role of crosstalk between the light and ABA signaling pathways in regulating different physiological processes has become increasingly evident. This includes regulation of germination and early seedling development, control of stomatal development and conductance, growth, and development of roots, buds, and branches, and regulation of flowering. Light and ABA signaling cascades have various convergence points at both DNA and protein levels. The molecular crosstalk involves several light signaling factors such as HY5, COP1, PIFs, and BBXs that integrate with ABA signaling components such as the PYL receptors and ABI5. In particular, ABI5 and PIF4 promoters are key 'hotspots' for integrating these two pathways. Plants acquired both light and ABA signaling pathways before they colonized land almost 500 million years ago. In this review, we discuss recent advances in the interplay of light and ABA signaling regulating plant development and provide an overview of the evolution of these two pathways., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology. 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.)

Plants grow complex root systems to extract unevenly distributed resources from soils. Spatial differences in soil moisture are perceived by root tips, leading to the patterning of new root branches toward available water in a process called hydropatterning. Little is known about hydropatterning behavior and its genetic basis in crop plants. Here, we developed an assay to measure hydropatterning in maize and revealed substantial differences between tropical/subtropical and temperate maize breeding germplasm that likely resulted from divergent selection. Genetic analysis of hydropatterning confirmed the regulatory role of auxin and revealed that the gaseous hormone ethylene locally inhibits root branching from air-exposed tissues. Our results demonstrate how distinct signaling pathways translate spatial patterns of water availability to developmental programs that determine root architecture.

Cardiovascular diseases represent the principal cause of death and comorbidity among people with diabetes. Ferroptosis, an iron-dependent non-apoptotic regulated cellular death characterized by lipid peroxidation, is involved in the pathogenesis of diabetic cardiovascular diseases. The susceptibility to ferroptosis in diabetic hearts is possibly related to myocardial iron accumulation, abnormal lipid metabolism and excess oxidative stress under hyperglycemia conditions. Accumulating evidence suggests ferroptosis can be the therapeutic target for diabetic cardiovascular diseases. This review summarizes ferroptosis-related mechanisms in the pathogenesis of diabetic cardiovascular diseases and novel therapeutic choices targeting ferroptosis-related pathways. Further study on ferroptosis-mediated cardiac injury can enhance our understanding of the pathophysiology of diabetic cardiovascular diseases and provide more potential therapeutic choices., Competing Interests: Declarations. Ethical approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Tendinopathies are debilitating diseases currently increasing in prevalence and associated costs. There is a need to deepen our understanding of the underlying cell signaling pathways to unlock effective treatments. In this work, we screen cell signaling pathways in human tendinopathies and find positively enriched IL-6/JAK/STAT signaling alongside signatures of cell populations typically activated by IL-6 in other tissues. In human tendinopathic tendons, we also confirm the strong presence and co-localization of IL-6, IL-6R, and CD90, an established marker of reparative fibroblasts. To dissect the underlying causalities, we combine IL-6 knock-out mice with an explant-based assembloid model of tendon damage to successfully connect IL-6 signaling to reparative fibroblast activation and recruitment. Vice versa, we show that these reparative fibroblasts promote the development of tendinopathy hallmarks in the damaged explant upon IL-6 activation. We conclude that IL-6 activates tendon fibroblast populations which then initiate and deteriorate tendinopathy hallmarks., Competing Interests: TS, GM, AH, PJ, KD, JS No competing interests declared, (© 2023, Stauber et al.)

Plants have developed complex mechanisms to perceive, transduce, and respond to environmental signals, such as light, which are essential for acquiring and allocating resources, including nitrogen (N). This review delves into the complex interaction between light signals and N metabolism, emphasizing light-mediated regulation of N uptake and assimilation. Firstly, we examine the details of light-mediated regulation of N uptake and assimilation, focusing on the light-responsive activity of nitrate reductase (NR) and nitrate transporters. Secondly, we discuss the influence of light on N-dependent developmental plasticity, elucidating how N availability regulates crucial developmental transitions such as flowering time, shoot branching, and root growth, as well as how light modulates these processes. Additionally, we consider the molecular interaction between light and N signalling, focusing on photoreceptors and transcription factors such as HY5, which are necessary for N uptake and assimilation under varying light conditions. A recent understanding of the nitrate signalling and perception of low N is also highlighted. The in silico transcriptome analysis suggests a reprogramming of N signalling genes by shade, and identifies NLP7, bZIP1, CPK30, CBL1, LBD37, LBD38, and HRS1 as crucial molecular regulators integrating light-regulated N metabolism., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology. 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.)

Significance: This work combines functional studies in model systems and examination of human tumor specimens to define a central oncogenic pathway driven by DNAJB1-PRKACA fusions in FLC. DNAJB1-PRKACA-mediated inactivation of the SIK stimulates CRTC2-p300-mediated transcription to drive tumor growth. The findings illuminate pathogenic mechanisms and inform therapeutic development., (©2024 The Authors; Published by the American Association for Cancer Research.)

The UV RESISTANCE LOCUS 8 (UVR8) photoreceptor mediates many plant responses to UV-B and short wavelength UV-A light. UVR8 functions through interactions with other proteins which lead to extensive changes in gene expression. Interactions with particular proteins determine the nature of the response to UV-B. It is therefore important to understand the molecular basis of these interactions: how are different proteins able to bind to UVR8 and how is differential binding regulated? This concise review highlights recent developments in addressing these questions. Key advances are discussed with regard to: identification of proteins that interact with UVR8; the mechanism of UVR8 accumulation in the nucleus; the photoactivation of UVR8 monomer; the structural basis of interaction between UVR8 and CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) and REPRESSOR OF UV-B PHOTOMORPHOGENESIS (RUP) proteins; and the role of UVR8 phosphorylation in modulating interactions and responses to UV-B. Nevertheless, much remains to be understood, and the need to extend future research to the growing list of interactors is emphasized., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

GIGANTEA (GI) is a multifaceted plant-specific protein that originated in a streptophyte ancestor. The current known functions of GI include circadian clock control, light signalling, flowering time regulation, stomata response, chloroplast biogenesis, accumulation of anthocyanin, chlorophyll, and starch, phytohormone signalling, senescence, and response to drought, salt, and oxidative stress. Six decades since its discovery, no functional domains have been defined, and its mechanism of action is still not well characterized. In this review, we explore the functional evolution of GI to distinguish between ancestral and more recently acquired roles. GI integrated itself into various existing signalling pathways of the circadian clock, blue light, photoperiod, and osmotic and oxidative stress response. It also evolved parallelly to acquire new functions for chloroplast accumulation, red light signalling, and anthocyanin production. In this review, we have encapsulated the known mechanisms of various biological functions of GI, and cast light on the evolution of GI in the plant lineage., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology. 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.)