Targeting MDM2 by disrupting its interaction with p53 or inhibiting its E3 ligase activity is a promising strategy to restore p53 functionality. However, achieving anticancer efficacy while minimizing dose-limiting toxicities remains a significant challenge. Moreover, MDM2 also ubiquitinates various non-p53 targets, complicating its therapeutic targeting. In this study, we demonstrate that MDM2 directly facilitates K48-linked polyubiquitination of MEIS1 at K178, leading to its proteasomal degradation. Notably, MEIS1 forms a non-competitive ternary complex with MDM2 and p53, effectively promoting ubiquitin transfer to itself and preventing p53 ubiquitination. The MEIS1 K178R mutant, which is deficient in ubiquitination, fails to suppress MDM2-mediated p53 ubiquitination, demonstrating a mechanistic link between MEIS1 self-ubiquitination and p53 stabilization. Furthermore, MDM2-mediated MEIS1 ubiquitination is a prerequisite for p53 activation in the DNA damage response. Importantly, a MEIS1-derived peptide, which mimics the MDM2-mediating ubiquitination motif, enhances both MEIS1 and p53 stability, suppresses cell proliferation and tumor growth. Collectively, our findings identify MEIS1 as a molecular decoy that competes for ubiquitin transfer to protect p53 and highlight that MEIS1 ubiquitination could be a novel therapeutic target for reactivating p53-dependent tumor suppression.
{"title":"Ubiquitination of MEIS1 by MDM2 serves as a switch for p53 stabilization and DNA damage response activation","authors":"Jiaxin Liu, Yanxia Duan, Qing Xiao, Shumin Deng, AiLin Li, Di Wu, Jingqiu Wu, Chang Liu, Hanxi Yi, Maonan Wang, Guang Shu, Gang Yin","doi":"10.1038/s41418-026-01714-9","DOIUrl":"https://doi.org/10.1038/s41418-026-01714-9","url":null,"abstract":"Targeting MDM2 by disrupting its interaction with p53 or inhibiting its E3 ligase activity is a promising strategy to restore p53 functionality. However, achieving anticancer efficacy while minimizing dose-limiting toxicities remains a significant challenge. Moreover, MDM2 also ubiquitinates various non-p53 targets, complicating its therapeutic targeting. In this study, we demonstrate that MDM2 directly facilitates K48-linked polyubiquitination of MEIS1 at K178, leading to its proteasomal degradation. Notably, MEIS1 forms a non-competitive ternary complex with MDM2 and p53, effectively promoting ubiquitin transfer to itself and preventing p53 ubiquitination. The MEIS1 K178R mutant, which is deficient in ubiquitination, fails to suppress MDM2-mediated p53 ubiquitination, demonstrating a mechanistic link between MEIS1 self-ubiquitination and p53 stabilization. Furthermore, MDM2-mediated MEIS1 ubiquitination is a prerequisite for p53 activation in the DNA damage response. Importantly, a MEIS1-derived peptide, which mimics the MDM2-mediating ubiquitination motif, enhances both MEIS1 and p53 stability, suppresses cell proliferation and tumor growth. Collectively, our findings identify MEIS1 as a molecular decoy that competes for ubiquitin transfer to protect p53 and highlight that MEIS1 ubiquitination could be a novel therapeutic target for reactivating p53-dependent tumor suppression.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"239 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147454756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diabetic complications frequently arise in mechanically stressed regions, yet the molecular links between biomechanical forces and metabolic dysfunction remain unclear. Here, we demonstrate that mechanical stress induces glucose accumulation and downstream metabolic stress in keratinocytes. Mechanistically, Piezo1 activation led to intracellular glucose overload and advanced glycation end-products (AGEs) accumulation, which induced mitochondrial DNA (mtDNA) leakage into the cytosol and subsequently activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling cascade (cGAS-STING pathway). Keratinocyte-specific Piezo1 deletion markedly reduced AGEs accumulation and preserved mitochondrial integrity, and STING ablation exhibited similar downstream protective effects. Notably, we identify Cortistatin (CST), an endogenous neuropeptide, as a previously unrecognized inhibitory ligand of Piezo1. CST binding attenuates calcium influx and glucose accumulation under mechanical stress, conferring notable protection in vitro and in diabetic ulcers (DUs) models. These findings uncover a CST-Piezo1-STING regulatory axis that integrates mechanical and metabolic cues to drive keratinocyte dysfunction in diabetes.
{"title":"Cortistatin antagonizes Piezo1-STING axis and facilitates mitochondrial homeostasis of keratinocytes by attenuating AGEs accumulation in diabetic ulcers","authors":"Guoli Ma, Qinghao Yuan, Yonggang Li, Ben Liu, Jingwei Bi, Mengfei Lv, Hang Li, Tengxiao Huang, Kaitian Yin, Wenke Zhao, Gaoxin Jin, Chuanju Liu, Krasimir Vasilev, Xinyu Liu, Yunpeng Zhao, Zhijian Wei, Weiwei Li","doi":"10.1038/s41418-026-01699-5","DOIUrl":"https://doi.org/10.1038/s41418-026-01699-5","url":null,"abstract":"Diabetic complications frequently arise in mechanically stressed regions, yet the molecular links between biomechanical forces and metabolic dysfunction remain unclear. Here, we demonstrate that mechanical stress induces glucose accumulation and downstream metabolic stress in keratinocytes. Mechanistically, Piezo1 activation led to intracellular glucose overload and advanced glycation end-products (AGEs) accumulation, which induced mitochondrial DNA (mtDNA) leakage into the cytosol and subsequently activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling cascade (cGAS-STING pathway). Keratinocyte-specific Piezo1 deletion markedly reduced AGEs accumulation and preserved mitochondrial integrity, and STING ablation exhibited similar downstream protective effects. Notably, we identify Cortistatin (CST), an endogenous neuropeptide, as a previously unrecognized inhibitory ligand of Piezo1. CST binding attenuates calcium influx and glucose accumulation under mechanical stress, conferring notable protection in vitro and in diabetic ulcers (DUs) models. These findings uncover a CST-Piezo1-STING regulatory axis that integrates mechanical and metabolic cues to drive keratinocyte dysfunction in diabetes.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"91 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147454755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Autoimmune uveitis (AU) lacks targeted therapies beyond immunosuppression. We identified hyodeoxycholate (HDCA), a gut-derived secondary bile acid, as a key immunometabolic regulator in AU. Metabolomics revealed systemic depletion of HDCA and oleic acid (C18:1n9) in AU patients and experimental AU (EAU) mice, correlating with disease severity. HDCA administration effectively attenuated EAU by reducing pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and elevating IL-10. Mechanistically, HDCA inhibits Farnesoid X Receptor in splenic red pulp macrophages, activating SREBP1c-dependent fatty acid synthase, which enhances oleic acid production. Systemic oleic acid suppresses ocular Th17 responses and promotes M2 macrophage polarization, enhancing anti-inflammatory immunity. These findings define a spleen-to-eye immunometabolic axis driven by HDCA-mediated macrophage reprogramming, positioning HDCA as a promising therapeutic for AU.
{"title":"Gut-derived hyodeoxycholate reprograms the spleen–eye immunometabolic axis to suppress autoimmune uveitis","authors":"Yitao Li, Weijia Zheng, Jiao Ma, Lu Liu, Xintong Yang, Junliang Kuang, Nickie Chan, Chengqiang Wang, Yang Li, Aihua Zhao, Ruonan Wang, Xiaojiao Zheng, Gerry Melino, Aiping Lu, Xiaolu Yang, Wei Jia","doi":"10.1038/s41418-026-01696-8","DOIUrl":"https://doi.org/10.1038/s41418-026-01696-8","url":null,"abstract":"Autoimmune uveitis (AU) lacks targeted therapies beyond immunosuppression. We identified hyodeoxycholate (HDCA), a gut-derived secondary bile acid, as a key immunometabolic regulator in AU. Metabolomics revealed systemic depletion of HDCA and oleic acid (C18:1n9) in AU patients and experimental AU (EAU) mice, correlating with disease severity. HDCA administration effectively attenuated EAU by reducing pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and elevating IL-10. Mechanistically, HDCA inhibits Farnesoid X Receptor in splenic red pulp macrophages, activating SREBP1c-dependent fatty acid synthase, which enhances oleic acid production. Systemic oleic acid suppresses ocular Th17 responses and promotes M2 macrophage polarization, enhancing anti-inflammatory immunity. These findings define a spleen-to-eye immunometabolic axis driven by HDCA-mediated macrophage reprogramming, positioning HDCA as a promising therapeutic for AU.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"33 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147394041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-07DOI: 10.1038/s41418-026-01698-6
Enwei Wei, Donglei Ji, Yanjie Jia, Ze Sun, Chunfeng Gao, Caroline Zeng, Chunyu Wang, Miaomiao Yu, Guanglei Shang, Linying Xie, Wenju Zhang, Yameng Li, Yingying Liang, Bai Ji, Yanzhu Yue, Yahui Liu, Ming-Ming Zhou, Lei Zeng
Histone lactylation couples glycolytic metabolism to oncogenic transcription, but its mechanistic readers remain poorly defined. Here, we identify bromodomain-containing protein 9 (BRD9) as a lactyl-lysine reader that links lactate-driven H3K18 lactylation (H3K18la) to chromatin remodeling in hepatocellular carcinoma (HCC). Clinically, elevated H3K18la levels correlate with poor HCC prognosis. Structural (NMR) and biophysical analyses demonstrate that BRD9's bromodomain engages H3K18la with weak, transient affinity through its conserved acetyl-lysine pocket, distinct from its stable H3K18ac binding. This enables BRD9 to function as a metabolic-epigenetic sensor, dynamically recruited to chromatin in response to glycolytic flux. Multi-omics profiling reveals that H3K18la recruits BRD9 and the non-canonical BRG1-associated factor (ncBAF) chromatin remodeling complex to active enhancers and promoters, promoting chromatin accessibility and driving oncogenic transcription (SPARC, TMEM64, ANGEL1, SCARB1). Glycolytic inhibition or BRD9 targeting displaces BRD9 from chromatin, suppresses oncogenes, and impairs HCC proliferation. Modulating the lactylation vis p300 or HDAC inhibition attenuates transcription and reduces tumor viability. In vivo, glycolytic inhibition suppresses tumor growth. Our findings establish a feedforward loop wherein glycolytic flux promotes H3K18la-dependent BRD9-ncBAF recruitment to remodel chromatin and sustain oncogenic transcription, defining BRD9 as a critical metabolic-epigenetic mediator and a promising therapeutic target in HCC.
{"title":"BRD9 recognizes lactate-induced H3K18 lactylation to drive oncogenic chromatin remodeling in hepatocellular carcinoma.","authors":"Enwei Wei, Donglei Ji, Yanjie Jia, Ze Sun, Chunfeng Gao, Caroline Zeng, Chunyu Wang, Miaomiao Yu, Guanglei Shang, Linying Xie, Wenju Zhang, Yameng Li, Yingying Liang, Bai Ji, Yanzhu Yue, Yahui Liu, Ming-Ming Zhou, Lei Zeng","doi":"10.1038/s41418-026-01698-6","DOIUrl":"https://doi.org/10.1038/s41418-026-01698-6","url":null,"abstract":"<p><p>Histone lactylation couples glycolytic metabolism to oncogenic transcription, but its mechanistic readers remain poorly defined. Here, we identify bromodomain-containing protein 9 (BRD9) as a lactyl-lysine reader that links lactate-driven H3K18 lactylation (H3K18la) to chromatin remodeling in hepatocellular carcinoma (HCC). Clinically, elevated H3K18la levels correlate with poor HCC prognosis. Structural (NMR) and biophysical analyses demonstrate that BRD9's bromodomain engages H3K18la with weak, transient affinity through its conserved acetyl-lysine pocket, distinct from its stable H3K18ac binding. This enables BRD9 to function as a metabolic-epigenetic sensor, dynamically recruited to chromatin in response to glycolytic flux. Multi-omics profiling reveals that H3K18la recruits BRD9 and the non-canonical BRG1-associated factor (ncBAF) chromatin remodeling complex to active enhancers and promoters, promoting chromatin accessibility and driving oncogenic transcription (SPARC, TMEM64, ANGEL1, SCARB1). Glycolytic inhibition or BRD9 targeting displaces BRD9 from chromatin, suppresses oncogenes, and impairs HCC proliferation. Modulating the lactylation vis p300 or HDAC inhibition attenuates transcription and reduces tumor viability. In vivo, glycolytic inhibition suppresses tumor growth. Our findings establish a feedforward loop wherein glycolytic flux promotes H3K18la-dependent BRD9-ncBAF recruitment to remodel chromatin and sustain oncogenic transcription, defining BRD9 as a critical metabolic-epigenetic mediator and a promising therapeutic target in HCC.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":15.4,"publicationDate":"2026-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147369389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-06DOI: 10.1038/s41418-026-01694-w
Arianna Chiesa, Vittoria Poli, Ottavio Croci, Francesca Biagioni, Patricio Fuentes, Mattia Marenda, Ambra Dondi, Simona Rodighiero, Marco Filipuzzi, Silvia Sberna, Matteo Marzi, Francesco Nicassio, Johannes Zuber, Stefano Campaner
YAP and TAZ are transcriptional regulators essential for mechanotransduction, development, and tissue homeostasis, whose dysregulation is implicated in multiple diseases, including cancer. To identify key regulators of YAP/TAZ signaling required for breast cancer cell fitness, we performed CRISPR/Cas9-based loss-of-function genetic screens both in vitro and in vivo. A custom sgRNA library targeting 216 candidate YAP/TAZ modulators was screened across three breast cancer cell lines. Among these, FERMT2, a component of the integrin signaling pathway, consistently emerged as a strong drop-out hit, highlighting its essential role in sustaining YAP/TAZ-dependent fitness. Bioinformatic analysis of large-scale cancer datasets further revealed genetic co-dependency between FERMT2, YAP, and TAZ, particularly in tumors with high YAP/TAZ expression. Functional validation through FERMT2 knockout and silencing demonstrated its requirement for proliferation, anchorage-independent growth, and tumorigenicity in triple-negative breast cancer cells. FERMT2 loss impaired YAP/TAZ nuclear accumulation, reduced the expression of YAP/TAZ target genes, and decreased phosphorylation at key tyrosine residues. Mechanistically, FERMT2 regulates YAP/TAZ independently of the canonical Hippo pathway through integrin-mediated activation of FAK. Consistent with this, glucocorticoid-driven FAK activation restored YAP/TAZ signaling in FERMT2-depleted cells. Partial epistasis analyses also indicate that FERMT2 modulates actin-dependent regulation of YAP/TAZ. Together, these findings identify FERMT2 as a pivotal upstream regulator of YAP/TAZ via FAK signaling, demonstrate that YAP/TAZ are principal effectors of integrin activity, and suggest that FERMT2 may represent a selective vulnerability in cancers with elevated YAP/TAZ signaling.
{"title":"Functional genomic screens uncover FERMT2 as a critical regulator of YAP/TAZ-driven tumorigenicity.","authors":"Arianna Chiesa, Vittoria Poli, Ottavio Croci, Francesca Biagioni, Patricio Fuentes, Mattia Marenda, Ambra Dondi, Simona Rodighiero, Marco Filipuzzi, Silvia Sberna, Matteo Marzi, Francesco Nicassio, Johannes Zuber, Stefano Campaner","doi":"10.1038/s41418-026-01694-w","DOIUrl":"https://doi.org/10.1038/s41418-026-01694-w","url":null,"abstract":"<p><p>YAP and TAZ are transcriptional regulators essential for mechanotransduction, development, and tissue homeostasis, whose dysregulation is implicated in multiple diseases, including cancer. To identify key regulators of YAP/TAZ signaling required for breast cancer cell fitness, we performed CRISPR/Cas9-based loss-of-function genetic screens both in vitro and in vivo. A custom sgRNA library targeting 216 candidate YAP/TAZ modulators was screened across three breast cancer cell lines. Among these, FERMT2, a component of the integrin signaling pathway, consistently emerged as a strong drop-out hit, highlighting its essential role in sustaining YAP/TAZ-dependent fitness. Bioinformatic analysis of large-scale cancer datasets further revealed genetic co-dependency between FERMT2, YAP, and TAZ, particularly in tumors with high YAP/TAZ expression. Functional validation through FERMT2 knockout and silencing demonstrated its requirement for proliferation, anchorage-independent growth, and tumorigenicity in triple-negative breast cancer cells. FERMT2 loss impaired YAP/TAZ nuclear accumulation, reduced the expression of YAP/TAZ target genes, and decreased phosphorylation at key tyrosine residues. Mechanistically, FERMT2 regulates YAP/TAZ independently of the canonical Hippo pathway through integrin-mediated activation of FAK. Consistent with this, glucocorticoid-driven FAK activation restored YAP/TAZ signaling in FERMT2-depleted cells. Partial epistasis analyses also indicate that FERMT2 modulates actin-dependent regulation of YAP/TAZ. Together, these findings identify FERMT2 as a pivotal upstream regulator of YAP/TAZ via FAK signaling, demonstrate that YAP/TAZ are principal effectors of integrin activity, and suggest that FERMT2 may represent a selective vulnerability in cancers with elevated YAP/TAZ signaling.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":15.4,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147369415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-05DOI: 10.1038/s41418-026-01679-9
Nannan Tang, Ruxue Mu, He Wang, Jiaying Wu, Jie Zhang, Di Huang, Yannan Han, Wenjian Li, Yuqing Chen, Xiang Li, Yilin Sun, Zifeng Zhang, Jinlu Zuo, Ying Hu, Yanan Yin, Yang Qu, Jinping Liu, Lei Jiao, Xue Liu, Haihai Liang, Ning Wang, Yunlong Bai, Yan Liu, Bin Wang, Dan Zhao, Yu Liu, Baofeng Yang
Dilated cardiomyopathy (DCM) was the most prevalent cardiomyopathy worldwide. Although ferroptosis has been implicated in cardiac pathogenesis, its regulatory mechanism in DCM remained poorly defined. In this study, we found that GIPC1 (GAIP/RGS19-interacting protein), a scaffolding protein, was significantly downregulated in cardiac tissues from DCM patients and doxorubicin (DOX)-induced DCM models. Integrated proteomic and lipidomic analysis revealed that cardiac-specific knockout of GIPC1 disrupted mitochondrial fatty acid metabolism, increased the abundance of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs), and ultimately promoted ferroptosis in cardiomyocytes. Both in vitro and in vivo experiments demonstrated that GIPC1 deficiency exacerbated ferroptosis and cardiac dysfunction in DOX-induced cardiomyopathy, whereas GIPC1 overexpression conferred protection against ferroptosis in DOX-induced cardiomyopathy. Mechanistically, co-immunoprecipitation mass spectrometry (Co-IP/MS) and molecular docking demonstrated that GIPC1 interacted with mitochondrial 2,4-dienoyl-CoA reductase (DECR1) via its PDZ domain. Surface plasmon resonance (SPR) analysis further confirmed a high-affinity direct binding between GIPC1 and DECR1 (KD = 16.3 nM). Co-IP and immunofluorescence (IF) demonstrated that GIPC1 facilitated actin-dependent transport of DECR1 into mitochondria, thereby maintaining redox homeostasis and suppressing ferroptosis. Consistently, DECR1 overexpression rescued GIPC1 ablation-induced ferroptosis by balancing redox homeostasis. Together, these results demonstrated that GIPC1 reduced cardiomyocyte susceptibility to ferroptosis by promoting mitochondrial translocation of DECR1 and remodeling lipid homeostasis, highlighting GIPC1/DECR1 axis as a potential therapeutic strategy for DCM. A schematic model illustrating the pathogenic cascade triggered by GIPC1 deficiency during DCM. In DCM, the expression level of GIPC1 was downregulated, thereby inhibiting actin-dependent transport of DECR1 into mitochondria, which remodeled lipid homeostasis and ultimately induced cardiomyocytes ferroptosis. Created with Figdraw.com.
{"title":"GIPC1 governed ferroptosis by regulating DECR1-modulating lipid homeostasis during dilated cardiomyopathy (DCM)","authors":"Nannan Tang, Ruxue Mu, He Wang, Jiaying Wu, Jie Zhang, Di Huang, Yannan Han, Wenjian Li, Yuqing Chen, Xiang Li, Yilin Sun, Zifeng Zhang, Jinlu Zuo, Ying Hu, Yanan Yin, Yang Qu, Jinping Liu, Lei Jiao, Xue Liu, Haihai Liang, Ning Wang, Yunlong Bai, Yan Liu, Bin Wang, Dan Zhao, Yu Liu, Baofeng Yang","doi":"10.1038/s41418-026-01679-9","DOIUrl":"https://doi.org/10.1038/s41418-026-01679-9","url":null,"abstract":"Dilated cardiomyopathy (DCM) was the most prevalent cardiomyopathy worldwide. Although ferroptosis has been implicated in cardiac pathogenesis, its regulatory mechanism in DCM remained poorly defined. In this study, we found that GIPC1 (GAIP/RGS19-interacting protein), a scaffolding protein, was significantly downregulated in cardiac tissues from DCM patients and doxorubicin (DOX)-induced DCM models. Integrated proteomic and lipidomic analysis revealed that cardiac-specific knockout of GIPC1 disrupted mitochondrial fatty acid metabolism, increased the abundance of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs), and ultimately promoted ferroptosis in cardiomyocytes. Both in vitro and in vivo experiments demonstrated that GIPC1 deficiency exacerbated ferroptosis and cardiac dysfunction in DOX-induced cardiomyopathy, whereas GIPC1 overexpression conferred protection against ferroptosis in DOX-induced cardiomyopathy. Mechanistically, co-immunoprecipitation mass spectrometry (Co-IP/MS) and molecular docking demonstrated that GIPC1 interacted with mitochondrial 2,4-dienoyl-CoA reductase (DECR1) via its PDZ domain. Surface plasmon resonance (SPR) analysis further confirmed a high-affinity direct binding between GIPC1 and DECR1 (KD = 16.3 nM). Co-IP and immunofluorescence (IF) demonstrated that GIPC1 facilitated actin-dependent transport of DECR1 into mitochondria, thereby maintaining redox homeostasis and suppressing ferroptosis. Consistently, DECR1 overexpression rescued GIPC1 ablation-induced ferroptosis by balancing redox homeostasis. Together, these results demonstrated that GIPC1 reduced cardiomyocyte susceptibility to ferroptosis by promoting mitochondrial translocation of DECR1 and remodeling lipid homeostasis, highlighting GIPC1/DECR1 axis as a potential therapeutic strategy for DCM.\u0000\u0000A schematic model illustrating the pathogenic cascade triggered by GIPC1 deficiency during DCM. In DCM, the expression level of GIPC1 was downregulated, thereby inhibiting actin-dependent transport of DECR1 into mitochondria, which remodeled lipid homeostasis and ultimately induced cardiomyocytes ferroptosis. Created with Figdraw.com.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"117 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neuromyelitis optica spectrum disorder (NMOSD) is recognized as a form of astrocytopathy; however, the mechanisms underlying aquaporin (AQP)4-IgG-induced astrocytic dysfunction remain to be fully elucidated. Here, single-nucleus RNA sequencing revealed that astrocytic ferroptosis is observed in mouse models of NMOSD, accompanied by expression alterations of multiple ferroptosis regulators. The activation of ferroptosis in astrocytes was further confirmed in in vitro NMOSD models through increased intracellular Fe²⁺ levels, lipid peroxidation, malondialdehyde, and lactate dehydrogenase levels, alongside reduced glutathione levels. Moreover, a remarkable increase in inflammatory reactive astrocytes was observed both in vivo and in vitro during NMOSD pathology. Notably, acyl-CoA synthetase long-chain family member 4 (ACSL4) upregulation in astrocytes was validated in NMOSD models. AQP4-IgG-induced ACSL4 upregulation was reversed by early growth response 1 (Egr1) siRNA. Suppressing ACSL4 expression mitigated astrocytic ferroptosis, reduced reactive astrocytes, attenuated demyelination, and ultimately improved NMOSD prognosis in mice. These findings demonstrate that ACSL4 mediates astrocytic ferroptosis, thereby contributing to NMOSD progression. Targeting ACSL4 may represent a promising astrocyte-directed therapeutic strategy for NMOSD.
{"title":"ACSL4-mediated astrocyte ferroptosis augments neuroinflammation and exacerbates NMOSD pathology","authors":"Haixia Wen, Yinyu Zi, Zhuhe Liu, Yunmeng Bai, Jingfang Lin, Haitao Wang, Bingtian Xu, Jigang Wang, Honghao Wang","doi":"10.1038/s41418-026-01692-y","DOIUrl":"https://doi.org/10.1038/s41418-026-01692-y","url":null,"abstract":"Neuromyelitis optica spectrum disorder (NMOSD) is recognized as a form of astrocytopathy; however, the mechanisms underlying aquaporin (AQP)4-IgG-induced astrocytic dysfunction remain to be fully elucidated. Here, single-nucleus RNA sequencing revealed that astrocytic ferroptosis is observed in mouse models of NMOSD, accompanied by expression alterations of multiple ferroptosis regulators. The activation of ferroptosis in astrocytes was further confirmed in in vitro NMOSD models through increased intracellular Fe²⁺ levels, lipid peroxidation, malondialdehyde, and lactate dehydrogenase levels, alongside reduced glutathione levels. Moreover, a remarkable increase in inflammatory reactive astrocytes was observed both in vivo and in vitro during NMOSD pathology. Notably, acyl-CoA synthetase long-chain family member 4 (ACSL4) upregulation in astrocytes was validated in NMOSD models. AQP4-IgG-induced ACSL4 upregulation was reversed by early growth response 1 (Egr1) siRNA. Suppressing ACSL4 expression mitigated astrocytic ferroptosis, reduced reactive astrocytes, attenuated demyelination, and ultimately improved NMOSD prognosis in mice. These findings demonstrate that ACSL4 mediates astrocytic ferroptosis, thereby contributing to NMOSD progression. Targeting ACSL4 may represent a promising astrocyte-directed therapeutic strategy for NMOSD.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"27 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-03DOI: 10.1038/s41418-026-01697-7
Yueqin Zhang, Lidong Cao, Xiao Wang, Lu Zhou, Weiyi Zhao, Mu He, Jun Tong, Qingqing Wu, Muhammad Umar, Junjie Qian, Xiaobin Fei, Jie Liu, Mengmeng Dong, Chengwu Zhang, Changwei Dou
YEATS2, a crucial component of histone acetyltransferase (HAT) complexes, has been identified as overexpressed in multiple human cancers and is correlated with tumor advancement and unfavorable clinical outcomes. The precise role of YEATS2 in hepatocellular carcinoma (HCC) remains to be fully elucidated. This study seeks to investigate the function and mechanisms by which YEATS2 facilitates HCC growth and metastasis. Our results demonstrate that YEATS2 expression is markedly elevated in HCC tissues and is correlated with unfavorable clinical characteristics and decreased survival rates. Functional assays conducted both in vitro and in vivo reveal that YEATS2 enhances HCC cell proliferation, migration, and invasion. Through RNA sequencing and mass spectrometry analyses, this study revealed YEATS2 activates the TAZ/AKT signaling pathway and promotes aerobic glycolysis via the upregulation of TGFBR2. Chromatin immunoprecipitation and co-immunoprecipitation assays further confirm that YEATS2 interacts with KAT2A, leading to increased levels of H3K9ac and H3K14ac within the promoter region of TGFBR2, thereby promoting its transcriptional activation. Moreover, increased matrix stiffness was found to induce YEATS2 expression through augmenting the binding of HIF-1α to the YEATS2 promoter. Collectively, these results delineate a novel YEATS2-TGFBR2-TAZ-AKT signaling axis that connects matrix stiffness to metabolic reprogramming and HCC progression, highlighting YEATS2 as a potential therapeutic target for HCC.
{"title":"Matrix stiffness-induced YEATS2 drives HCC progression via epigenetic activation of the TGFBR2-TAZ-AKT pathway","authors":"Yueqin Zhang, Lidong Cao, Xiao Wang, Lu Zhou, Weiyi Zhao, Mu He, Jun Tong, Qingqing Wu, Muhammad Umar, Junjie Qian, Xiaobin Fei, Jie Liu, Mengmeng Dong, Chengwu Zhang, Changwei Dou","doi":"10.1038/s41418-026-01697-7","DOIUrl":"https://doi.org/10.1038/s41418-026-01697-7","url":null,"abstract":"YEATS2, a crucial component of histone acetyltransferase (HAT) complexes, has been identified as overexpressed in multiple human cancers and is correlated with tumor advancement and unfavorable clinical outcomes. The precise role of YEATS2 in hepatocellular carcinoma (HCC) remains to be fully elucidated. This study seeks to investigate the function and mechanisms by which YEATS2 facilitates HCC growth and metastasis. Our results demonstrate that YEATS2 expression is markedly elevated in HCC tissues and is correlated with unfavorable clinical characteristics and decreased survival rates. Functional assays conducted both in vitro and in vivo reveal that YEATS2 enhances HCC cell proliferation, migration, and invasion. Through RNA sequencing and mass spectrometry analyses, this study revealed YEATS2 activates the TAZ/AKT signaling pathway and promotes aerobic glycolysis via the upregulation of TGFBR2. Chromatin immunoprecipitation and co-immunoprecipitation assays further confirm that YEATS2 interacts with KAT2A, leading to increased levels of H3K9ac and H3K14ac within the promoter region of TGFBR2, thereby promoting its transcriptional activation. Moreover, increased matrix stiffness was found to induce YEATS2 expression through augmenting the binding of HIF-1α to the YEATS2 promoter. Collectively, these results delineate a novel YEATS2-TGFBR2-TAZ-AKT signaling axis that connects matrix stiffness to metabolic reprogramming and HCC progression, highlighting YEATS2 as a potential therapeutic target for HCC.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"54 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sepsis, a life-threatening systemic inflammatory condition, frequently leads to myocardial injury-a complication for which current therapeutic strategies demonstrate limited efficacy. Here, we explored the potential role and therapeutic implications of Deltex E3 ubiquitin ligase 2 (DTX2) in sepsis-induced myocardial injury. Our results demonstrated that DTX2 expression was significantly upregulated in septic patients, mice models, and lipopolysaccharide (LPS)-stimulated cardiomyocytes. Notably, Dtx2 deficiency markedly aggravated sepsis-induced myocardial hypertrophy, fibrosis, ferroptosis, and mitochondrial dysfunction. In contrast, cardiac-specific overexpression of Dtx2 improved cardiac function in vivo, highlighting its protective role in septic cardiomyopathy. Mechanistically, DTX2 was found to directly interact with transferrin receptor 1 (TfR1) through its DTC domain, mediating K27-linked ubiquitination at lysine 39, which facilitated TfR1 degradation and regulated iron metabolism. Importantly, pharmacological inhibition of ferroptosis counteracted the detrimental effects of Dtx2 deficiency in both LPS-challenged cells and mice. Moreover, genetic silencing of TfR1 considerably suppressed ferroptosis and ameliorated myocardial injury in Dtx2 knockout septic mice. The findings indicate that DTX2 exerts protective effects against abnormal iron accumulation and ferroptosis, thereby alleviating myocardial injury induced by sepsis. These insights could have therapeutic implications for patients with reduced DTX2 expression.
{"title":"Deltex E3 ubiquitin ligase 2 prevents sepsis-induced myocardial injury through degrading TfR1 via promoting K27-linked ubiquitination.","authors":"Chang Liu, Jia Liu, Mingchen Yin, Runze Li, Caihong Fan, Yixing Chen, Lihong Guo, Zhi Qi, Yanna Shen","doi":"10.1038/s41418-026-01690-0","DOIUrl":"https://doi.org/10.1038/s41418-026-01690-0","url":null,"abstract":"<p><p>Sepsis, a life-threatening systemic inflammatory condition, frequently leads to myocardial injury-a complication for which current therapeutic strategies demonstrate limited efficacy. Here, we explored the potential role and therapeutic implications of Deltex E3 ubiquitin ligase 2 (DTX2) in sepsis-induced myocardial injury. Our results demonstrated that DTX2 expression was significantly upregulated in septic patients, mice models, and lipopolysaccharide (LPS)-stimulated cardiomyocytes. Notably, Dtx2 deficiency markedly aggravated sepsis-induced myocardial hypertrophy, fibrosis, ferroptosis, and mitochondrial dysfunction. In contrast, cardiac-specific overexpression of Dtx2 improved cardiac function in vivo, highlighting its protective role in septic cardiomyopathy. Mechanistically, DTX2 was found to directly interact with transferrin receptor 1 (TfR1) through its DTC domain, mediating K27-linked ubiquitination at lysine 39, which facilitated TfR1 degradation and regulated iron metabolism. Importantly, pharmacological inhibition of ferroptosis counteracted the detrimental effects of Dtx2 deficiency in both LPS-challenged cells and mice. Moreover, genetic silencing of TfR1 considerably suppressed ferroptosis and ameliorated myocardial injury in Dtx2 knockout septic mice. The findings indicate that DTX2 exerts protective effects against abnormal iron accumulation and ferroptosis, thereby alleviating myocardial injury induced by sepsis. These insights could have therapeutic implications for patients with reduced DTX2 expression.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":15.4,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147343498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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