Cell Death Discovery最新文献

{"title":"Low extracellular pH protects cancer cells from ammonia toxicity.","authors":"Maria Dravecka, Ingvild Mikkola, Terje Johansen, Ole Morten Seternes, Jakob Mejlvang","doi":"10.1038/s41420-025-02440-w","DOIUrl":"10.1038/s41420-025-02440-w","url":null,"abstract":"<p><p>Ammonia is a natural waste product of cellular metabolism which, through its lysosomotropic ability, can have detrimental effects on various cellular functions. Increased levels of ammonia were recently detected in the interstitial fluid of various tumours, substantiating that high ammonia concentrations are a pathophysiological condition in the tumour microenvironment, alongside hypoxia and acidosis. Since little is known about how cancer cells respond to elevated levels of ammonia in the tumour microenvironment, we investigated how a panel of cancer cell lines derived from solid tumours behaved when exposed to increasing concentrations of ammonia. We found that ammonia represses cell growth, induces genome instability, and inhibits lysosome-mediated proteolysis in a dose-dependent manner. Unexpectedly, we also found that small fluctuations in the pH of the extracellular environment, had a significant impact on the cytotoxic effects of ammonia. In summary, our data show that the balance of pH and ammonia within the interstitial fluids of cancerous tumours significantly impacts the behaviour and fate of cells residing in the tumour microenvironment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"137"},"PeriodicalIF":6.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the potential of selective FKBP51 inhibitors on melanoma: an investigation of their in vitro and in vivo effects.","authors":"Laura Marrone, Valeria Di Giacomo, Chiara Malasomma, Marialuisa Alessandra Vecchione, Felix Hausch, Massimiliano Cacace, Lucia D'Esposito, Martina Tufano, Paolo D'Arrigo, Maria Fiammetta Romano, Simona Romano","doi":"10.1038/s41420-025-02430-y","DOIUrl":"10.1038/s41420-025-02430-y","url":null,"abstract":"<p><p>FKBP51 is a marker of melanocyte malignancy, correlating with vertical growth phase and lesion thickness. It promotes the typical features of epithelial to mesenchymal transition and sustains apoptosis resistance. The present study aimed to assess in vitro and in vivo the efficacy against melanoma of selective small molecules targeting FKBP51, called SAFits. Our findings reveal differing outcomes for SAFits in vitro compared to in vivo. SAFit increased the doxorubicin and dacarbazine cytotoxicity of cultured melanoma cells and was effective in impairing NF-κB activity and related pro-survival genes. Moreover, SAFit affected TGF-β-signaling and reduced the capability of melanoma cells to migrate through transwell filters and invade the matrigel. Unexpectedly, SAFit was ineffective in reducing tumor growth in a syngeneic melanoma mouse model. A study of the tumor microenvironment revealed an enrichment of M2 macrophages in SAFit-treated mice. Western blot assay showed reduced levels of perforin in protein extracted from SAFit-treated tumor samples. Ex-vivo experiments showed that M1 and M2 macrophages exerted an opposite effect on the cytotoxic capacity of CD8 T cells, supporting the hypothesis that enrichment in M2 macrophages induced by SAFit could accelerate the exhaustion of CD8 lymphocytes. In conclusion, our study shows that selective FKBP51 targeting agents hinder the intrinsic pro-survival pathways of melanoma cells but simultaneously exacerbate immune suppression within the tumor microenvironment, and, therefore, they have not proven to be effective in vivo to counteract melanoma growth.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"138"},"PeriodicalIF":6.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The involvement of TRPV1 in the apoptosis of spermatogenic cells in the testis of mice with cryptorchidism.","authors":"Yanqiu Zhao, Jinhua Wei, Pang Cheng, Junxian Ma, Bo Liu, Mingxiang Xiong, Ting Gao, Jingqi Yao, Tianchen Sun, Zhen Li","doi":"10.1038/s41420-025-02447-3","DOIUrl":"10.1038/s41420-025-02447-3","url":null,"abstract":"<p><p>Cryptorchidism is associated with an increased risk of male infertility and testicular cancer. Persistent exposure to high temperature in cryptorchidism can lead to the apoptosis of spermatogenic cells. Transient receptor potential vanilloid 1 (TRPV1), a thermosensitive cation channel, has been found to have differential effects on various apoptosis processes. However, whether TRPV1 is involved in spermatogenic cell apoptosis induced by cryptorchidism remains unclear. Herein, we first observed the expression pattern of TRPV1 in the testes of mice with experimental cryptorchidism, and then investigated the role and mechanism of TRPV1 in spermatogenic cell apoptosis by using Trpv1^-/- mice. The results showed that TRPV1 was highly expressed on the membrane of spermatocytes in mouse testis, and the expression increased significantly in the testis of mice with experimental cryptorchidism. After the operation, Trpv1^-/- mice exhibited less reproductive damage and fewer spermatogenic cell apoptosis compared to the wild-type (WT) mice. Transcriptome sequencing revealed that the expression of apoptosis-related genes (Capn1, Capn2, Bax, Aifm1, Caspase 3, Map3k5, Itpr1 and Fas) was down-regulated in spermatocytes of cryptorchid Trpv1^-/- mice. Our results suggest that TRPV1 promotes the apoptosis of spermatocytes in cryptorchid mice by regulating the expression of apoptosis-related genes.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"135"},"PeriodicalIF":6.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual role of p21 in regulating apoptosis and mitotic integrity in response to doxorubicin in colon cancer cells.","authors":"Heeyeon Kim, Haein Kim, Eunjung Jang, Young-Woo Eom, Gyesoon Yoon, Kyeong Sook Choi, Eunhee Kim","doi":"10.1038/s41420-025-02416-w","DOIUrl":"10.1038/s41420-025-02416-w","url":null,"abstract":"<p><p>This study explores the multifaceted role of p21 in mediating cellular responses to DNA-damaging agents, with a focus on doxorubicin treatment in HCT116 colon carcinoma cells. We investigated how different doses of doxorubicin affect cells with varied p21 and p53 statuses, revealing distinct roles for p21 depending on the drug dosage. At high doses (HD), p21 is more critical than p53 in mediating apoptosis, whereas at low doses (LD), p21 is essential for preventing mitotic defects and multinucleation. Notably, reintroducing p21 or pharmacologically inhibiting CDK1 reduced multinucleation. The absence of p21 upon LD doxorubicin exposure led to aberrant chromosome segregation, persistent DNA damage response (DDR) activation, and increased non-homologous end-joining (NHEJ) activity, resulting in unrepaired DNA accumulation and multinucleation. Additionally, mitotic defects in p21-deficient cells were associated with mislocalization of key mitotic regulators, Aurora B and mitotic kinesin-like protein 1 (MKLP1), exacerbating defective mitosis. In summary, p21 functions as a dual regulator in response to DNA damage, promoting apoptosis at HD and preventing mitotic failure at LD. These insights have significant implications for cancer therapy, highlighting the potential of targeting the p21 to enhance treatment efficacy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"133"},"PeriodicalIF":6.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering UBE4B phosphorylation dynamics: a key mechanism in p53 accumulation and cancer cell response to DNA damage.","authors":"Yasser Abuetabh, H Helena Wu, Habib Al Yousef, Sujata Persad, Mary-Pat Schlosser, David D Eisenstat, Consolato M Sergi, Roger Leng","doi":"10.1038/s41420-025-02441-9","DOIUrl":"10.1038/s41420-025-02441-9","url":null,"abstract":"<p><p>The p53 tumor suppressor protein plays a crucial role in detecting and eliminating various oncogenic threats by promoting processes such as cell cycle arrest, DNA repair, senescence, and apoptosis. UBE4B is essential for negatively regulating p53 during normal conditions and following DNA damage. In previous studies, we demonstrated that UBE4B targets phosphorylated p53 for degradation in response to DNA damage. However, the regulation of UBE4B in relation to DNA damage in cancer is not well understood. In this study, we show that the UBE4B protein is regulated through a phosphorylation and dephosphorylation mechanism in response to DNA damage. Phosphorylation of UBE4B reduces its binding affinity to p53, leading to an accumulation of p53 in the cell. Wip1 plays a crucial role in the dephosphorylation of UBE4B, which stabilizes the activity of the UBE4B protein in response to DNA damage. UBE4B is primarily phosphorylated through ATR-mediated signaling, which reduces its binding affinity with p53, resulting in the accumulation and activation of p53. When Wip1 is inhibited, there is a significant increase in UBE4B phosphorylation, leading to more p53 accumulation and a reduction in cell growth. Therefore, understanding how UBE4B is regulated in cancer cells in response to DNA-damaging agents could help develop new therapeutic strategies to improve the prognosis for cancer patients.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"131"},"PeriodicalIF":6.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ABCB1 confers resistance to carboplatin by accumulating stem-like cells in the G2/M phase of the cell cycle in p53^null ovarian cancer.","authors":"Danbi Lee, Hyun-Seok Jeong, Sun-Young Hwang, Yu-Gyeong Lee, Youn-Jung Kang","doi":"10.1038/s41420-025-02435-7","DOIUrl":"10.1038/s41420-025-02435-7","url":null,"abstract":"<p><p>High-grade ovarian serous carcinoma, mostly bearing the various mutations in the TP53 gene, typically relapses within six months after first-line therapy due to chemoresistance, with a median overall survival of less than a year. However, the molecular mechanisms of action behind acquired drug resistance, particularly in relation to different TP53 mutation types, have not been fully elucidated. In this study, we demonstrated that acquired resistance to carboplatin in SKOV3 harboring a p53^null mutation, but not in OVCAR3 with a p53^R248Q, induces a significant portion of cells accumulated in the G2/M phase of the cell cycle, where cells highly expressed stemness marker with elevated proliferative capacity, which we believe was reversed by ABCB1 inhibition to the levels observed in non-resistant parental cells. ABCB1 suppression re-sensitized carboplatin-resistant cells to additional genotoxic stress and reduced their proliferative ability by recovering DNA repair activity and lowering stemness-like features, especially in the G2/M-distributed fraction. This suggests that high levels of stemness and attenuated DNA repair function exhibited in the G2/M-accumulated portion may be a key contributor of chemoresistance in patients with ovarian cancer bearing a p53^null mutation, but not other types of mutations expressing p53. Furthermore, the inhibition of ΔNp73 resulted in the suppression of ABCB1, which consequently restricted cell growth in carboplatin-resistant SKOV3, suggesting that the ΔNp73 may act as an upstream regulator of the ABCB1. Notably, combinatorial treatment of carboplatin with the p53 reactivator, APR-246, proved effective in overcoming chemoresistance in OVCAR3 with the p53^R248Q. Our findings suggest that the ΔNp73-ABCB1 axis is a promising molecular target for carboplatin-resistant ovarian cancers harboring p53^null mutations, which we uncovered could be utilized to increase the efficacy of conventional anti-cancer therapies, to develop more efficient combinatorial therapeutic interventions directed toward overcoming the chemoresistance and improving the survival rates in patients with ovarian cancer.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"132"},"PeriodicalIF":6.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex and age differences in glia and myelin in nonhuman primate and human spinal cords: implications for pathology.","authors":"Gaëtan Poulen, Nacéra Douich, Chloé M Gazard, Nadine Mestre-Francés, Maïda Cardoso, Luc Bauchet, Florence Vachiery-Lahaye, Nicolas Lonjon, Yannick N Gerber, Florence E Perrin","doi":"10.1038/s41420-025-02425-9","DOIUrl":"10.1038/s41420-025-02425-9","url":null,"abstract":"<p><p>In a healthy central nervous system, glial cells are influenced by genetic, epigenetic, age, and sex factors. Aging typically causes astrocytes and microglia to undergo changes that reduce their neuroprotective functions and increase harmful activities. Additionally, sex-related differences in glial and myelin functions may impact neurological disorders. Despite this, few studies have investigated glial cells in primates, with most focusing on the brain. This study aims to explore whether glial cells and myelin exhibit age- and sex-related differences in the spinal cord of nonhuman primates and humans. We used immunohistochemistry and myelin staining to analyze healthy spinal cord samples from midlife and aged individuals of both sexes, focusing on Microcebus murinus (a small nonhuman primate) and humans. Primate spinal cords show distinct variations in glial markers and myelin characteristics related to sex and age, with differences varying between species. Notably, GFAP expression is sex-dependent in both primate species. We also observed greater differences in the expression of microglial markers than other glial markers. Overall, we found the opposite pattern for the g-ratio and oligodendrocytic marker between species. These findings suggest that glial cells may play a critical role in age- and sex-related differences in the prevalence and progression of spinal cord diseases.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"129"},"PeriodicalIF":6.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting KIF18A triggers antitumor immunity and enhances efficiency of PD-1 blockade in colorectal cancer with chromosomal instability phenotype.","authors":"Gang Liu, Yan Zhang, Zhen Cao, Zhanwei Zhao","doi":"10.1038/s41420-025-02437-5","DOIUrl":"10.1038/s41420-025-02437-5","url":null,"abstract":"<p><p>Colorectal cancer with chromosomal instability (CIN⁺) phenotype is immunosuppressive and refractory to immune checkpoint blockade (ICB) therapy. Recently, KIF18A is found to be a mitotic vulnerability in chromosomally unstable cancers, but whether targeting KIF18A affects antitumor immunity in CIN⁺ colorectal cancer is unknown. In our study, western blot, cell viability assay, transwell migration and invasion assays, flow cytometry, animal model, immunohistochemistry (IHC) staining, reverse transcription-quantitative PCR (RT-qPCR) and ELISA assay were conducted to evaluate the potential function of KIF18A in CIN⁺ colorectal cancer. We found that KIF18A inhibition by short hairpin RNAs (ShRNAs) or small inhibitor AM-1882 suppressed proliferation, migration, invasion and tumor growth and metastasis of CIN⁺ colorectal cancer cells in vitro and in vivo. Moreover, targeting KIF18A disrupted cell-cycle progression and induced G2/M arrest in CIN⁺ colorectal cancer cells. In addition, KIF18A inhibition promoted immune infiltration and activation in CIN⁺ colorectal tumors. KIF18A inhibition suppressed proliferation of Tregs and increased infiltration and activation of cytotoxic CD8⁺ T cells in CIN⁺ colorectal tumors. Mechanically, KIF18A inhibition stimulated type I IFN signaling and cGAS-STING activation in CIN⁺ colorectal tumors. Finally, targeting KIF18A enhanced PD-1 blockade efficiency in CIN⁺ colorectal tumors through T cells. Our data elucidated a novel role of KIF18A in antitumor immunity of CIN⁺ colorectal cancer.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"130"},"PeriodicalIF":6.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis: CD8⁺T cells' blade to destroy tumor cells or poison for self-destruction.","authors":"Yuan Liang, Yixin Zhao, Zhaoyang Qi, Xinru Li, Yuguang Zhao","doi":"10.1038/s41420-025-02415-x","DOIUrl":"10.1038/s41420-025-02415-x","url":null,"abstract":"<p><p>Ferroptosis represents an emerging, iron-dependent form of cell death driven by lipid peroxidation. In recent years, it has garnered significant attention in the realm of cancer immunotherapy, particularly in studies involving immune checkpoint inhibitors. This form of cell death not only enhances our comprehension of the tumor microenvironment but is also considered a promising therapeutic strategy to address tumor resistance, investigate immune activation mechanisms, and facilitate the development of cancer vaccines. The combination of immunotherapy with ferroptosis provides innovative targets and fresh perspectives for advancing cancer treatment. Nevertheless, tumor cells appear to possess a wider array of ferroptosis evasion strategies compared to CD8⁺T cells, which have been conclusively shown to be more vulnerable to ferroptosis. Furthermore, ferroptosis in the TME can create a favorable environment for tumor survival and invasion. Under this premise, both inducing tumor cell ferroptosis and inhibiting T cell ferroptosis will impact antitumor immunity to some extent, and even make the final result run counter to our therapeutic purpose. This paper systematically elucidates the dual-edged sword role of ferroptosis in the antitumor process of T cells, briefly outlining the complexity of ferroptosis within the TME. It explores potential side effects associated with ferroptosis-inducing therapies and critically considers the combined application of ferroptosis-based therapies with ICIs. Furthermore, it highlights the current challenges faced by this combined therapeutic approach and points out future directions for development.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"128"},"PeriodicalIF":6.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin-induced gene 2 alleviates ischemia-reperfusion injury in steatotic liver by inhibiting GPX4-dependent ferroptosis.","authors":"Yichao Wu, Changbiao Li, Di Lu, Kangchen Chen, Renyi Su, Shengjun Xu, Fengqiang Gao, Zhengxing Lian, Fan Yang, Jun Chen, Fangqiang Wei, Xiao Xu, Zhikun Liu","doi":"10.1038/s41420-025-02406-y","DOIUrl":"10.1038/s41420-025-02406-y","url":null,"abstract":"<p><p>Hepatic steatosis significantly elevates the vulnerability of the graft to ischemia-reperfusion (I/R) injury during liver transplantation (LT). We investigated the protective role of insulin-induced gene 2 (Insig2) in steatotic liver's I/R injury and underlying mechanisms. Employing mouse model with Insig2 knock-out or hepatocyte-specific overexpression and high-fat diets to induce steatosis, we subjected these mice to hepatic I/R injury. The primary hepatocytes isolated from steatotic liver were used in in vitro hypoxia/reoxygenation (H/R) experiment. Our integrated in vivo and in vitro approach uncovered that Insig2 deficiency exacerbated steatotic liver's damage following hepatic I/R injury, whereas its overexpression offers protection. Mechanically, integrative analysis of transcriptome, proteome, and metabolome found that Insig2 deficiency disturbed lipid metabolism and oxidative stress homeostasis, particularly inhibiting GPX4 expression to induce ferroptosis. Furthermore, chemical inhibition of ferroptosis reversed the deleterious effect of Insig2 deficiency; whereas the protective influence of Insig2 overexpression was negated by the target inhibition of GPX4, leading to an exacerbation of hepatic I/R damage. These insights underscored the potential of the Insig2-GPX4 axis as a therapeutic target, presenting a novel avenue for enhancing the resilience of steatotic liver grafts against I/R injury.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"127"},"PeriodicalIF":6.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}