Pub Date : 2025-11-29DOI: 10.1038/s41418-025-01629-x
Zhihao Xu, Li Zhuang, Boyi Gan
{"title":"FABP5 drives ferroptosis in psoriasis","authors":"Zhihao Xu, Li Zhuang, Boyi Gan","doi":"10.1038/s41418-025-01629-x","DOIUrl":"https://doi.org/10.1038/s41418-025-01629-x","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"124 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614164","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 : 2025-11-28DOI: 10.1038/s41418-025-01621-5
Anwarul Ferdous, Ariel Diaz, Daniel Daou, Diana Dad Zada, Nan Jiang, Herman I. May, Juan A. Daniel-Olivas, Jan-Bernd Funcke, Mayarling F. Troncoso, Jafet Ortiz-Quintero, Magda C. Diaz-Vesga, Lorena Garcia, Mario Chiong, Dian J. Cao, Thomas G. Gillette, Sergio Lavandero, Joseph A. Hill
Vascular cell adhesion molecule 1 (VCAM-1), a known downstream target of the Forkhead box O (FoxO) family of transcription factors, has well-established roles in development, cell-cell interactions, and cell survival. However, the specific role and mechanisms whereby VCAM-1 governs cardiomyocyte homeostasis in ischemic heart disease are incompletely understood. Here, we report that ischemia/reperfusion (I/R)-induced myocardial damage resulted in marked attenuation of FoxO1 and Vcam1 mRNA levels in wild-type (WT) mice, suggesting a protective role of the FoxO1/VCAM-1 axis in I/R injury. Indeed, compared with WT littermates, cardiomyocyte-specific loss of Vcam1 significantly exacerbated I/R-induced myocardial damage, apoptotic cardiomyocyte death, contractile dysfunction, and maladaptive cardiac remodeling. We go on to show that after exposure to ischemia, Vcam1-deficient cardiomyocytes (both in vivo and in vitro) manifested marked attenuation of essential pro-survival cues. These include a decrease in the cardiomyocyte-leukocyte interaction-mediated induction of Ezrin and its downstream Akt and ERK1/2 phosphorylation, as well as decreased expression of tumor necrosis factor α (TNFα) and manganese superoxide dismutase 2 (Sod2) genes. Collectively, our findings uncover a VCAM-1/Ezrin axis as an essential and previously unrecognized protective mediator of cardiomyocyte homeostasis in ischemic myocardium.
{"title":"VCAM-1/Ezrin axis antagonizes myocardial damage in ischemia-reperfusion injury","authors":"Anwarul Ferdous, Ariel Diaz, Daniel Daou, Diana Dad Zada, Nan Jiang, Herman I. May, Juan A. Daniel-Olivas, Jan-Bernd Funcke, Mayarling F. Troncoso, Jafet Ortiz-Quintero, Magda C. Diaz-Vesga, Lorena Garcia, Mario Chiong, Dian J. Cao, Thomas G. Gillette, Sergio Lavandero, Joseph A. Hill","doi":"10.1038/s41418-025-01621-5","DOIUrl":"https://doi.org/10.1038/s41418-025-01621-5","url":null,"abstract":"Vascular cell adhesion molecule 1 (VCAM-1), a known downstream target of the Forkhead box O (FoxO) family of transcription factors, has well-established roles in development, cell-cell interactions, and cell survival. However, the specific role and mechanisms whereby VCAM-1 governs cardiomyocyte homeostasis in ischemic heart disease are incompletely understood. Here, we report that ischemia/reperfusion (I/R)-induced myocardial damage resulted in marked attenuation of FoxO1 and Vcam1 mRNA levels in wild-type (WT) mice, suggesting a protective role of the FoxO1/VCAM-1 axis in I/R injury. Indeed, compared with WT littermates, cardiomyocyte-specific loss of Vcam1 significantly exacerbated I/R-induced myocardial damage, apoptotic cardiomyocyte death, contractile dysfunction, and maladaptive cardiac remodeling. We go on to show that after exposure to ischemia, Vcam1-deficient cardiomyocytes (both in vivo and in vitro) manifested marked attenuation of essential pro-survival cues. These include a decrease in the cardiomyocyte-leukocyte interaction-mediated induction of Ezrin and its downstream Akt and ERK1/2 phosphorylation, as well as decreased expression of tumor necrosis factor α (TNFα) and manganese superoxide dismutase 2 (Sod2) genes. Collectively, our findings uncover a VCAM-1/Ezrin axis as an essential and previously unrecognized protective mediator of cardiomyocyte homeostasis in ischemic myocardium.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"19 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614165","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}
In mammalian cells, MCM2 and POLE3/4 safeguard the symmetrical segregation of parental histones to the leading and lagging strands of newly synthesized DNA. However, the identity of additional proteins involved in parental histone distribution remains elusive. We used TurboID proximity labeling to identify interaction partners of MCM2 and POLE3/4 in mouse cells. This approach provided a candidate protein library potentially involved in the MCM2 and POLE3/POLE4-mediated process of parental histone segregation. DNA polymerase δ subunit 3 (POLD3) was a protein whose intensity differed between the interactomes of wild-type MCM2 and its histone-binding mutant. We showed POLD3 bound to both MCM2 and the histone (H3-H4) 2 tetramers. Moreover, MCM2’s histone binding affected interactions between POLD3 and histone H3. More importantly, POLD3 was required for the symmetrical transfer of parental histones H3-H4 to the leading and lagging strands of newly synthesized DNA in mouse cells. In short, our findings establish that POLD3 forms a protein complex with MCM2 and histone (H3-H4) 2 tetramers, functioning as a novel histone chaperone to regulate parental histone segregation in mammalian cells.
{"title":"Proximal proteomics analysis reveals DNA polymerase δ subunit 3 is a new MCM2 binding partner and promotes parental histones inheritance in mammalian cells","authors":"Yaping Sun, Xiaoyan Liang, Fang Liu, Wenjuan Zhao, Jiaqi Zhou, Yue Li, Yuan Yao, Ziwei Zhang, Gang Li, Kuiming Chan, Daoqin Zhang, Zhiquan Wang, Yuan Gao, Chuanhe Yu, Yuchun Wu, Xing Kang, Lingyu Qiu, Nan Li, Haiyun Gan","doi":"10.1038/s41418-025-01619-z","DOIUrl":"https://doi.org/10.1038/s41418-025-01619-z","url":null,"abstract":"In mammalian cells, MCM2 and POLE3/4 safeguard the symmetrical segregation of parental histones to the leading and lagging strands of newly synthesized DNA. However, the identity of additional proteins involved in parental histone distribution remains elusive. We used TurboID proximity labeling to identify interaction partners of MCM2 and POLE3/4 in mouse cells. This approach provided a candidate protein library potentially involved in the MCM2 and POLE3/POLE4-mediated process of parental histone segregation. DNA polymerase δ subunit 3 (POLD3) was a protein whose intensity differed between the interactomes of wild-type MCM2 and its histone-binding mutant. We showed POLD3 bound to both MCM2 and the histone (H3-H4) <jats:sub>2</jats:sub> tetramers. Moreover, MCM2’s histone binding affected interactions between POLD3 and histone H3. More importantly, POLD3 was required for the symmetrical transfer of parental histones H3-H4 to the leading and lagging strands of newly synthesized DNA in mouse cells. In short, our findings establish that POLD3 forms a protein complex with MCM2 and histone (H3-H4) <jats:sub>2</jats:sub> tetramers, functioning as a novel histone chaperone to regulate parental histone segregation in mammalian cells.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"175 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145611570","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}
The tumor suppressor BRCA1-associated protein 1 (BAP1) encodes a nuclear deubiquitinase that specifically removes H2A monoubiquitination at Lys119 (H2Aub) and plays a crucial role in the epigenetic regulation of gene expression through cooperating with several transcriptional factors and chromatin-modifying enzymes. Our previous studies have confirmed that BAP1 represses SLC7A11-mediated cystine metabolism and promotes ferroptosis-dependent tumor suppression. However, how BAP1 regulates gene expression at the genome level and whether additional mechanisms are involved in the BAP1 regulation of ferroptosis remain unclear. Here, we integrate multi-omics analyses to explore the effects of BAP1-mediated H2Aub deubiquitination on the regulation of chromatin accessibility and gene transcription. Notably, we identified a novel target gene, ACSL4, which is positively regulated by BAP1 and contributes to BAP1-mediated ferroptosis. Importantly, genetic knockout or pharmacological inhibition of ACSL4 prevents the upregulation of lipid biosynthesis and ferroptotic cell death caused by BAP1. In addition, we demonstrated that BAP1-mediated regulation of gene expression and ferroptosis is dependent on ASXL family members instead of other BAP1-associated factors like FOXK1/2, HCFC1, and OGT. Together, our findings uncover a previously unappreciated epigenetic mechanism underlying the regulation of ACSL4 by H2A monoubiquitination, which connects ACSL4-mediated lipid metabolism to ferroptosis driven by BAP1, providing new insights into the understanding of metabolic regulation of BAP1-related diseases such as cancers.
肿瘤抑制因子BRCA1-associated protein 1 （BAP1）编码核去泛素酶，特异性去除Lys119位点的H2A单泛素化（H2Aub），并通过与多种转录因子和染色质修饰酶合作，在基因表达的表观遗传调控中发挥重要作用。我们之前的研究证实BAP1抑制slc7a11介导的胱氨酸代谢，促进铁中毒依赖性肿瘤抑制。然而，BAP1如何在基因组水平调控基因表达，以及BAP1对铁下垂的调控是否涉及其他机制尚不清楚。在这里，我们结合多组学分析来探讨bap1介导的H2Aub去泛素化对染色质可及性和基因转录调控的影响。值得注意的是，我们发现了一个新的靶基因ACSL4，该基因受BAP1的正调控，并参与BAP1介导的铁下垂。重要的是，基因敲除或药理抑制ACSL4可防止BAP1引起的脂质生物合成上调和铁致细胞死亡。此外，我们证明了bap1介导的基因表达和铁凋亡的调节依赖于ASXL家族成员，而不是其他bap1相关因子，如FOXK1/2、HCFC1和OGT。总之，我们的研究结果揭示了H2A单泛素化调控ACSL4的一个以前未被认识到的表观遗传机制，该机制将ACSL4介导的脂质代谢与BAP1驱动的铁死亡联系起来，为理解BAP1相关疾病（如癌症）的代谢调节提供了新的见解。
{"title":"Epigenetic regulation of ACSL4 via H2A monoubiquitylation connects lipid metabolism to BAP1-mediated ferroptosis","authors":"Kexin Fan, Shuting Zhou, Yakun Ren, Jingwen Xiong, Hua Wang, Yaxin Fu, Yuhan Chen, Bobo Wang, Kun Fan, Min Gao, Tingli Guo, Xiaofeng Wei, Lianying Jiao, Jiejun Shi, Chenguang Ding, Yilei Zhang","doi":"10.1038/s41418-025-01624-2","DOIUrl":"https://doi.org/10.1038/s41418-025-01624-2","url":null,"abstract":"The tumor suppressor BRCA1-associated protein 1 (BAP1) encodes a nuclear deubiquitinase that specifically removes H2A monoubiquitination at Lys119 (H2Aub) and plays a crucial role in the epigenetic regulation of gene expression through cooperating with several transcriptional factors and chromatin-modifying enzymes. Our previous studies have confirmed that BAP1 represses SLC7A11-mediated cystine metabolism and promotes ferroptosis-dependent tumor suppression. However, how BAP1 regulates gene expression at the genome level and whether additional mechanisms are involved in the BAP1 regulation of ferroptosis remain unclear. Here, we integrate multi-omics analyses to explore the effects of BAP1-mediated H2Aub deubiquitination on the regulation of chromatin accessibility and gene transcription. Notably, we identified a novel target gene, ACSL4, which is positively regulated by BAP1 and contributes to BAP1-mediated ferroptosis. Importantly, genetic knockout or pharmacological inhibition of ACSL4 prevents the upregulation of lipid biosynthesis and ferroptotic cell death caused by BAP1. In addition, we demonstrated that BAP1-mediated regulation of gene expression and ferroptosis is dependent on ASXL family members instead of other BAP1-associated factors like FOXK1/2, HCFC1, and OGT. Together, our findings uncover a previously unappreciated epigenetic mechanism underlying the regulation of ACSL4 by H2A monoubiquitination, which connects ACSL4-mediated lipid metabolism to ferroptosis driven by BAP1, providing new insights into the understanding of metabolic regulation of BAP1-related diseases such as cancers.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"20 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609205","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 : 2025-11-26DOI: 10.1038/s41418-025-01623-3
Ine Koeken, Magali Walravens, Roberto Fernández-Acosta, Ruben Van Hoyweghen, Iuliana Vintea, Yingyi Kong, Bianka Golba, Jonas Dehairs, Ali Talebi, Johannes V. Swinnen, Kaat Durinck, Adriana Mañas, Shinya Toyokuni, Gerben Menschaert, Maria Fedorova, Bruno G. De Geest, Behrouz Hassannia, Tom Vanden Berghe
Ferroptosis—an iron-dependent form of cell death triggered by phospholipid peroxidation—has emerged as a promising therapeutic avenue in cancer treatment. Although neuroblastoma (NB) has been identified as a ferroptosis susceptible cancer, our studies reveal striking heterogeneity in ferroptosis sensitivity across high-risk NB models. Through a targeted metabolic compound screen, we identified stearoyl-CoA desaturase 1 (SCD1)—a key enzyme in monounsaturated fatty acid (MUFA) synthesis—as a robust ferroptosis-sensitizing target. Genetic and pharmacological inhibition of SCD1 restored ferroptosis sensitivity in resistant NB cells. Notably, high SCD1 expression correlates with poor patient prognosis. Co-treatment with arachidonic acid (AA), a polyunsaturated fatty acid (PUFA), further enhanced ferroptotic cell death via increased PUFA/MUFA ratio. Nevertheless, neither baseline lipidomic profiles nor transcriptomes of key ferroptosis regulators reliably predicted ferroptosis sensitivity. To overcome AA’s poor solubility, we engineered AA-loaded lipid nanoparticles (AA-LNPs), which selectively accumulated in high-risk NB tumors and synergized with SCD1 inhibition. This dual-sensitization strategy, termed LipidSens, significantly suppressed tumor growth and induced ferroptosis in cell-derived xenograft mouse models without systemic toxicity. Together, these findings establish MUFA synthesis blockade and PUFA enrichment as a tumor-targeted, ferroptosis-enhancing strategy, and offer a nanomedicine-based therapeutic platform for high-risk NB.
{"title":"Dual lipid modulation overcomes ferroptosis resistance in high-risk neuroblastoma","authors":"Ine Koeken, Magali Walravens, Roberto Fernández-Acosta, Ruben Van Hoyweghen, Iuliana Vintea, Yingyi Kong, Bianka Golba, Jonas Dehairs, Ali Talebi, Johannes V. Swinnen, Kaat Durinck, Adriana Mañas, Shinya Toyokuni, Gerben Menschaert, Maria Fedorova, Bruno G. De Geest, Behrouz Hassannia, Tom Vanden Berghe","doi":"10.1038/s41418-025-01623-3","DOIUrl":"https://doi.org/10.1038/s41418-025-01623-3","url":null,"abstract":"Ferroptosis—an iron-dependent form of cell death triggered by phospholipid peroxidation—has emerged as a promising therapeutic avenue in cancer treatment. Although neuroblastoma (NB) has been identified as a ferroptosis susceptible cancer, our studies reveal striking heterogeneity in ferroptosis sensitivity across high-risk NB models. Through a targeted metabolic compound screen, we identified stearoyl-CoA desaturase 1 (SCD1)—a key enzyme in monounsaturated fatty acid (MUFA) synthesis—as a robust ferroptosis-sensitizing target. Genetic and pharmacological inhibition of SCD1 restored ferroptosis sensitivity in resistant NB cells. Notably, high SCD1 expression correlates with poor patient prognosis. Co-treatment with arachidonic acid (AA), a polyunsaturated fatty acid (PUFA), further enhanced ferroptotic cell death via increased PUFA/MUFA ratio. Nevertheless, neither baseline lipidomic profiles nor transcriptomes of key ferroptosis regulators reliably predicted ferroptosis sensitivity. To overcome AA’s poor solubility, we engineered AA-loaded lipid nanoparticles (AA-LNPs), which selectively accumulated in high-risk NB tumors and synergized with SCD1 inhibition. This dual-sensitization strategy, termed LipidSens, significantly suppressed tumor growth and induced ferroptosis in cell-derived xenograft mouse models without systemic toxicity. Together, these findings establish MUFA synthesis blockade and PUFA enrichment as a tumor-targeted, ferroptosis-enhancing strategy, and offer a nanomedicine-based therapeutic platform for high-risk NB.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"16 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609460","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 : 2025-11-25DOI: 10.1038/s41418-025-01618-0
Ismael Sánchez-Vera, Ana M. Cosialls, Nekane Maritorena-Hualde, Max-Hinderk Schuler, Rodolfo Lavilla, Gabriel Pons, Lucas T. Jae, Daniel Iglesias-Serret, Joan Gil
{"title":"Targeting prohibitins activates the ISR through DELE1-HRI by impairing protein import into the mitochondrial matrix","authors":"Ismael Sánchez-Vera, Ana M. Cosialls, Nekane Maritorena-Hualde, Max-Hinderk Schuler, Rodolfo Lavilla, Gabriel Pons, Lucas T. Jae, Daniel Iglesias-Serret, Joan Gil","doi":"10.1038/s41418-025-01618-0","DOIUrl":"https://doi.org/10.1038/s41418-025-01618-0","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"120 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599436","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 : 2025-11-24DOI: 10.1038/s41418-025-01622-4
Yonghwan Shin, Sungmin Kim, Suhn K. Rhie, Woojin An
{"title":"HDAC1 has intrinsic protease activity and regulates transcription through clipping histone H3 N-terminal tail","authors":"Yonghwan Shin, Sungmin Kim, Suhn K. Rhie, Woojin An","doi":"10.1038/s41418-025-01622-4","DOIUrl":"https://doi.org/10.1038/s41418-025-01622-4","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"187 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583229","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 : 2025-11-21DOI: 10.1038/s41418-025-01625-1
Runa Wang, Guizhi Guo, Renshuai Zhang, Lin Li, Yingxin Gong, Long Yin, Shuhua Li, Changfeng Wei, Jun Zhou, Min Liu, Jie Ran
{"title":"UFL1-mediated UFMylation antagonizes IFT88 ubiquitination and degradation to maintain ciliary homeostasis","authors":"Runa Wang, Guizhi Guo, Renshuai Zhang, Lin Li, Yingxin Gong, Long Yin, Shuhua Li, Changfeng Wei, Jun Zhou, Min Liu, Jie Ran","doi":"10.1038/s41418-025-01625-1","DOIUrl":"https://doi.org/10.1038/s41418-025-01625-1","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"186 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559931","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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