Biochimica et biophysica acta. Molecular cell research最新文献

{"title":"USP47 enhances NRP1-mediated angiogenesis to promote gastric cancer progression","authors":"Wei Chen ,&nbsp;Huizhi Wang ,&nbsp;Haitao Sun ,&nbsp;Junbo Zuo ,&nbsp;Pengcheng Jiang ,&nbsp;Wen Feng ,&nbsp;Zhenhua Huang","doi":"10.1016/j.bbamcr.2025.120004","DOIUrl":"10.1016/j.bbamcr.2025.120004","url":null,"abstract":"<div><div>Gastric cancer (GC) is a leading cause of cancer-related mortality, particularly in East Asia, where its incidence remains high. The limited prognosis for advanced GC patients underscores the need for new therapeutic strategies targeting key molecules involved in tumor progression. In this study, we investigated the role of the deubiquitinating enzyme USP47 in GC progression, focusing on its interaction with Neuropilin-1 (NRP1), a co-receptor known to enhance angiogenesis. Our findings reveal that USP47 is significantly overexpressed in GC tissues and correlates with poor patient survival. Through in vitro experiments, we demonstrate that USP47 promotes GC cell proliferation, migration, and invasion. Additionally, USP47 enhances angiogenesis by stabilizing NRP1, preventing its ubiquitination and degradation, and activating the PI3K/Akt signaling pathway. These results suggest that USP47 contributes to GC progression through the regulation of NRP1-mediated angiogenesis, highlighting its potential as a therapeutic target for GC treatment.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 120004"},"PeriodicalIF":4.6,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144241428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming MET-targeted drug resistance in MET-amplified lung cancer by aurora kinase B inhibition","authors":"Yu-Ra Choi ,&nbsp;Mihwa Hwang ,&nbsp;Jaemin Kim ,&nbsp;Seog-Yun Park ,&nbsp;Sunshin Kim ,&nbsp;Jae J. Song ,&nbsp;Youngjoo Lee","doi":"10.1016/j.bbamcr.2025.120001","DOIUrl":"10.1016/j.bbamcr.2025.120001","url":null,"abstract":"<div><div>MET-targeted therapies are the most effective treatment for patients with <em>MET</em>-amplified lung cancer. However, acquired drug resistance is a significant challenge in <em>MET</em>-amplified lung cancer treatment. This study aimed to discover an effective treatment strategy for overcoming MET-targeted drug resistance. We first established a lung cancer cell line resistant to MET tyrosine kinase inhibitor (MET-TKI) (H1993 PR-S2) from <em>MET</em>-amplified lung cancer cells (H1993). High-throughput screening using an anti-cancer compound library identified Aurora Kinase B (AURKB) inhibitor as a potent agent suppressing H1993 PR-S2 cell viability. In these resistant cells, p-MET expression was markedly decreased, while p-AURKB was significantly increased. Furthermore, STAT3-activated gene signatures were enriched in H1993 PR-S2 cells, and p-STAT3 expression was closely linked to AURKB. The AURKB overexpression induced p-STAT3 activation in the parental cells, whereas the AURKB knockdown reduced p-STAT3 expression in the H1993 PR-S2 cells. The resistant cells showed increased BCL2 gene expression, and STAT3-BCL2 expression was highly suppressed by AURKB inhibitor. However, MET-TKI sensitivity was not enhanced by STAT3 or BCL2 knockdown in H1993 PR-S2 cells. Additionally, the elevated expression of cleavage-caspase3 and the G2/M phase arrest were observed at lower concentrations of AURKB inhibitor in the H1993 PR-S2 cells. AURKB inhibitor also showed potent anti-tumor activity against the H1993 PR-S2 tumor xenografts. Finally, we confirmed the upregulated AURKB and p-STAT3 expression in post-treatment tumors of advanced <em>MET</em>-amplified lung cancer patient who experienced acquired resistance to MET-targeted drugs. These findings suggest AURKB is a potential druggable target for MET-TKI-resistant <em>MET</em>-amplified lung cancer treatment.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 120001"},"PeriodicalIF":4.6,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144253977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of PARL-mediated mitochondrial protease activity on calcium regulation","authors":"Donato D'Angelo ,&nbsp;Aya Al Saidi ,&nbsp;Giorgia Ghirardo ,&nbsp;Denis Vecellio Reane ,&nbsp;Nicola Gasparini ,&nbsp;Rosario Rizzuto ,&nbsp;Anna Raffaello","doi":"10.1016/j.bbamcr.2025.119998","DOIUrl":"10.1016/j.bbamcr.2025.119998","url":null,"abstract":"<div><div>The presenilin-associated rhomboid-like protein (PARL) is a mitochondrial inner membrane serine protease that is a key regulator of several cellular processes, including apoptosis, metabolism, inflammation and stress responses. While recent studies suggest that PARL may play a role in mitochondrial calcium homeostasis, the underlying mechanisms remain poorly understood. In this study, we investigated the effects of PARL modulation on mitochondrial and cytosolic calcium dynamics, as well as mitochondrial membrane potential. Our results show that altering PARL protein levels, through both overexpression and silencing, significantly affects mitochondrial calcium uptake, without influencing cytosolic calcium transients or mitochondrial membrane potential. Despite the observed changes in mitochondrial calcium dynamics, PARL does not interact with the mitochondrial calcium uniporter complex (mtCU) regulators MICU1 and MICU2, which are critical for regulating mitochondrial calcium influx. However, we observed alterations in the protein levels of MICU1 and MICU2, either in their monomeric or dimeric forms, suggesting that PARL may influence these mtCU components indirectly. Interestingly, the pore-forming subunit MCU, and the structural subunit EMRE, essential for the assembly of the mtCU, were unaffected by PARL modulation. These findings suggest that the role of PARL in modulating mitochondrial calcium homeostasis may involve indirect mechanisms, potentially involving other regulatory pathways. Overall, our study provides novel insights into the functional role of PARL in mitochondrial calcium regulation, offering potential avenues for further investigation into its broader cellular functions.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 119998"},"PeriodicalIF":4.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISP3-PSP94 complex regulates P2RX7 mediated signalling in prostate cancer cells and macrophages via CITED2","authors":"Vaidehi Miya,&nbsp;Bhakti R. Pathak","doi":"10.1016/j.bbamcr.2025.119997","DOIUrl":"10.1016/j.bbamcr.2025.119997","url":null,"abstract":"<div><div>CRISP3 (Cysteine rich secretory protein 3) and PSP94 (Prostate secretory protein of 94 amino acids) are evolutionarily conserved proteins that form high affinity complexes. They show an inverse expression pattern during prostate tumorigenesis and are linked to poor prognosis. Apart from prostate, they are present in various body fluids and are speculated to contribute to innate immunity, however their role in tumor immune microenvironment remains uninvestigated. In our earlier study, P2RX7, an ATP-gated ion channel and an important player in the inflammasome pathway, was amongst the genes upregulated upon CRISP3 knockdown. We investigated it further and demonstrated that exogenously added rhCRISP3 downregulated P2RX7 levels in PC3 cells and THP1 macrophages. Interestingly, this effect was abrogated when it was complexed with PSP94. CRISP3 mediated P2RX7 downregulation also reduced ATP-induced cytotoxicity and IL-1β secretion, which was reversed in the presence of PSP94. PSP94 also affected endocytosis of CRISP3 and its interaction with flotillin-2. Using an antibody array, CITED2, a transcriptional coregulator was identified as a downstream mediator of CRISP3. Overexpression of CITED2 also downregulated P2RX7. Since CITED2 modulates transcription through p300 availability, presence of p300 at P2RX7 promoter in PC3 cells and THP1 macrophages was confirmed by CUT&amp;RUN assay. CITED2 overexpression led to reduced p300 levels which could be the reason for downregulation of P2RX7. Our findings unravel a novel mechanism linking CRISP3-PSP94-P2RX7 with CITED2. CRISP3 overexpression and PSP94 downregulation in prostate tumors may influence the tumor immune microenvironment by regulating P2RX7 and CITED2 levels in tumor cells and tumor-associated macrophages.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 119997"},"PeriodicalIF":4.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomic profiling reveals grade-specific niacinamide accumulation and its therapeutic potential via SIRT1-CD38-EMT axis modulation in cervical cancer progression","authors":"Shivani Jaiswal ,&nbsp;Vivek Mishra ,&nbsp;Srija Majumder ,&nbsp;Pramod P. Wangikar ,&nbsp;Shinjinee Sengupta","doi":"10.1016/j.bbamcr.2025.119994","DOIUrl":"10.1016/j.bbamcr.2025.119994","url":null,"abstract":"<div><div>Despite new therapies for cervical cancer, innovative strategies are essential to overcome drug resistance and high toxicity. The present study focuses on the metabolic profiling of cervical carcinoma using a non-targeted metabolomics approach using liquid chromatography-mass spectrometry. Our study identified over 70 metabolites in cervical tissue samples (both cancerous and adjacent normal) using HILIC and reversed-phase chromatography in the positive and negative ionization modes. Major metabolic alterations included changes in nicotinamide metabolism, ammonia recycling, amino acid metabolism and nucleotide metabolism, in a grade-dependent manner. Compared to normal tissue, HPV-positive tumors showed elevated nicotinamide metabolism, and phosphatidylethanolamine biosynthesis, whereas HPV-negative tumors showed enriched purine and pyrimidine metabolism. We validated our findings by analyzing transcriptomics datasets from the Gene Expression Omnibus database to understand the expression patterns of the underlying genes involved in the dysregulated pathways. We observed that nicotinamide metabolism exhibits significant effects in lower-grade cervical cancers and specific HPV genotypes. We treated cervical cancer cell lines with niacinamide (NAM), an amide form of niacin, to evaluate its therapeutic efficacy. NAM treatment modulated NAD⁺ metabolism, affecting key players such as CD38, PARP, NAMPT, and SIRT1, promoting apoptosis and inhibiting cell proliferation in cervical cancer cells. Importantly, HPV-positive SiHa cells showed elevated NAD⁺ metabolism relative to HPV-negative C33A cells, reflecting distinct metabolic adaptations that may influence tumor progression. The study highlights the metabolic shifts in cancer progression and provides insights into NAM's molecular mechanisms and therapeutic potential for precision medicine in cervical cancer.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 119994"},"PeriodicalIF":4.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144213291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MitoQ for vitiligo by mitigating PARP1 translocation aberrations: Network pharmacology and experimental validation","authors":"Renxue Xiong ,&nbsp;Shiyu Jin ,&nbsp;Yujie Li ,&nbsp;Tingru Dong ,&nbsp;Xiuzu Song ,&nbsp;Cuiping Guan","doi":"10.1016/j.bbamcr.2025.119995","DOIUrl":"10.1016/j.bbamcr.2025.119995","url":null,"abstract":"<div><h3>Purpose</h3><div>Oxidative stress plays a significant role in the development of vitiligo. Although the specific mechanism of the mitochondria-targeted antioxidant mitoquinone (MitoQ) in vitiligo remains unclear, it has shown promise in the treatment of various diseases.</div></div><div><h3>Methods</h3><div>In this study, we employed network pharmacology, molecular docking, transcriptomic approaches, and experimental verification to investigate the potential targets of MitoQ in vitiligo.</div></div><div><h3>Results</h3><div>Molecular docking results identified four possible crucial targets of MitoQ in vitiligo treatment: poly (ADP-ribose) polymerase 1 (PARP1), prostaglandin-endoperoxide synthase 2 (PTGS2), estrogen receptor 1 (ESR1), and C-X-C motif chemokine receptor 3 (CXCR3). MitoQ alleviated oxidative stress-induced PARP1 nuclear mislocalization, attenuated ROS accumulation, restored mitochondrial membrane potential, and enhanced ATP synthesis in vitro analysis. Transcriptomic analysis demonstrated that MitoQ reduced the expression of DNA damage genes and genes involved in the PI3K-AKT and MAPK signaling pathways. The protein-protein interaction network indicated a potential relationship between PARP1 and DNA damage-related genes, suggesting that MitoQ could interfere with abnormal PARP1 activation. Notably, MitoQ reduced cellular senescence by decreasing CDKN1A/p21 protein through PARP1, and the knockdown of PARP1 reduced oxidative damage.</div></div><div><h3>Conclusion</h3><div>These results indicate that PARP1 decreases cellular senescence and offers a potential target for therapeutic research in the management of vitiligo.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 119995"},"PeriodicalIF":4.6,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144189305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oscillatory shear stress activates integrin β3, blocking autophagic flux in endothelial cells and promoting endothelial cells senescence","authors":"Shuai Li ,&nbsp;Xingyu Jiang ,&nbsp;Wenjun Huang ,&nbsp;Qingyu Meng ,&nbsp;Luya Pu ,&nbsp;Banghao Sun ,&nbsp;Bin Liu ,&nbsp;Fan Li","doi":"10.1016/j.bbamcr.2025.119991","DOIUrl":"10.1016/j.bbamcr.2025.119991","url":null,"abstract":"<div><div>Atherosclerosis is an age-related cardiovascular disease. The intersections and bends of blood vessels under the direct action of oscillatory shear stress (OSS) are susceptible to atherosclerotic plaque formation, and the expression of age-related factors is significantly increased in plaques. However, the molecular mechanism by which OSS promotes vascular senescence is still unclear. In this study, we found that the expression of age-related factors, such as P16 and P21, was increased in human aortic endothelial cells (HAECs) exposed to OSS. We also found that the expression of autophagy-related gene 5 (ATG5), microtubule-associated protein 1 light chain 3β (MAP1LC3B), and beclin 1 (BECN1) was increased in HAECs exposed to OSS. The expression of sequestosome-1 (SQSTM1/P62) was also increased. Immunofluorescence confirmed that OSS impaired autophagic flux in HAECs by inhibiting the binding of autophagosomes to lysosome, thereby promoting endothelial cell (EC) senescence. The OSS-sensitive gene integrin β3 (ITGB3), which is closely related to EC autophagy and senescence, was screened by proteomics analysis of HAECs in the control and OSS-treated groups. The protein and mRNA expression of ITGB3 was significantly increased in HAECs exposed to OSS. ITGB3 overexpression in HAECs significantly affected the autophagic flux of ECs and promoted EC senescence, resulting in an increase in cells in the G0/G1 phase and cell cycle arrest. ITGB3 knockdown significantly inhibited the block of OSS-induced autophagic flux and senescence in ECs. In addition, in vivo studies showed that treatment with the ITGB3 inhibitor Cyclo(arginine-glycine-aspartate-tyrosine-lysine) [Cyclo(RGDyK)] significantly inhibited high-fat diet-induced plaque formation in the aortae of apolipoprotein E (ApoE)−/− mice. In conclusion, OSS blocks HAECs autophagic flux and promotes senescence via ITGB3 activation, thereby affecting the development of atherosclerosis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 7","pages":"Article 119991"},"PeriodicalIF":4.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA polymerase III transcription machinery and tRNA processing are regulated by the ubiquitin ligase Rsp5","authors":"Aleksandra Łopusińska,&nbsp;Michał Tys,&nbsp;Magdalena Boguta,&nbsp;Małgorzata Cieśla","doi":"10.1016/j.bbamcr.2025.119993","DOIUrl":"10.1016/j.bbamcr.2025.119993","url":null,"abstract":"<div><div>Transfer RNA (tRNA) biogenesis in yeast involves synthesis of the primary transcript by RNA polymerase III (Pol III), followed by processing to remove 5′ and 3′ ends, further maturation, and export to the cytoplasm. In the present study, we found that both tRNA transcription and the initial processing of tRNA precursors are affected by the ubiquitin ligase Rsp5. We observed high levels of unprocessed primary tRNA transcripts in <em>rsp5</em> mutants at elevated temperature, which were reduced upon the overexpression of <em>RPR1</em>, the catalytic subunit of RNase P. This observation suggests a role for Rsp5 in the maturation of 5′ ends of tRNA precursors. Under the same conditions, in vivo labeling showed that the amount of newly synthesized tRNA decreased. Furthermore, we found that Rsp5 directly interacted with the Tfc3 subunit of the TFIIIC transcription factor, which is modified by ubiquitination. The inactivation of Rsp5 catalytic activity influenced the interaction between the general Pol III factors TFIIIB and TFIIIC and decreased the recruitment of TFIIIC to tRNA genes. These findings suggest that Rsp5 ligase is implicated in the control of Pol III transcription in yeast.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119993"},"PeriodicalIF":4.6,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144115480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia-induced phenotypic transformation of scleral fibroblasts promotes activation of the adhesion patch pathway through paracrine effects leading to choroidal damage","authors":"Yuezu Li ,&nbsp;Ou Zhang ,&nbsp;Yanting Pan,&nbsp;Xueling Du,&nbsp;Jun Li","doi":"10.1016/j.bbamcr.2025.119992","DOIUrl":"10.1016/j.bbamcr.2025.119992","url":null,"abstract":"<div><div>Myopia has become an important cause of vision loss, where its prevalence is increasing in the younger population. The pathogenesis of myopia remains poorly understood. In this study, human scleral fibroblasts (HSFs) were induced by hypoxia to verify the effects of hypoxia on the phenotypic transformation and extracellular matrix remodeling of HSFs. Subsequently, exosomes of HSFs under normoxic and hypoxic conditions were extracted and validated to explore the effects of HSFs on human choroidal endothelial cells (HCEC). Transcriptome sequencing analyzed the possible molecular mechanisms by which HSFs affect HCEC. The results showed that hypoxia resulted in reduced proliferative capacity of HSFs, promoted cellular fibrosis as well as aggravated oxidative damage. The HCEC group treated with hypoxia-induced HSFs conditioned medium or exosomes exhibited significantly more cellular damage compared to the normal conditioned group. Transcriptome sequencing showed that differentially expressed genes in hypoxia-induced HSFs-derived exosome-treated HCEC were significantly enriched in the Focal adhesion signaling pathway. This sequencing result was verified by RT-qPCR and Western blot experiments. Our study demonstrated in vitro that hypoxia induces phenotypic transformation of HSFs, and that lead to HCEC damage through a paracrine mechanism, a process that may be mediated by the adhesion patch signaling pathway.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119992"},"PeriodicalIF":4.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPX4 degradation contributes to heat stress-induced liver injury via chaperone-mediated autophagy","authors":"Ting Wang,&nbsp;Xiao Liu,&nbsp;Xinyu Feng,&nbsp;Zhenyu Zhang,&nbsp;Ruiyi Lv,&nbsp;Wenhong Feng,&nbsp;Yukun Zhou,&nbsp;Xueyu Liao,&nbsp;Haoming Tang,&nbsp;Ming Xu","doi":"10.1016/j.bbamcr.2025.119988","DOIUrl":"10.1016/j.bbamcr.2025.119988","url":null,"abstract":"<div><div>Heat stress (HS) is a significant health concern that adversely affects both human and animal health, particularly impacting liver function due to its central metabolic role. This study investigated the mechanisms underlying HS-induced liver injury, focusing on the role of ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation and cellular iron accumulation. Using mouse and cellular HS models, the results demonstrated that HS induced liver injury through ferroptosis, as evidenced by increased levels of malondialdehyde (MDA), oxidized glutathione (GSSG), and iron, alongside decreased glutathione (GSH) and glutathione peroxidase 4 (GPX4) expression. The ferroptosis inhibitor Ferrostatin-1 (Fer-1) effectively mitigated HS-induced liver damage, reducing oxidative stress and restoring GPX4 levels. Furthermore, HS promoted the lysosomal degradation of GPX4 via the chaperone-mediated autophagy (CMA) pathway, which was regulated by heat shock cognate protein 70 (HSC70) and lysosome-associated membrane protein 2A (LAMP2A). Knockdown of LAMP2A in hepatocytes significantly suppressed HS-induced GPX4 degradation, confirming the critical role of CMA in this process. Inhibition of CMA using Apoptozole, an HSC70 inhibitor, or Bafilomycin A1 (Baf-A1), a lysosomal inhibitor, further attenuated HS-induced ferroptosis and liver injury. These findings highlight the critical role of CMA-mediated GPX4 degradation in HS-induced ferroptosis and liver injury, providing potential therapeutic targets for mitigating HS-related liver damage.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119988"},"PeriodicalIF":4.6,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143947612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}