Cell Death and Differentiation最新文献

{"title":"The histone modifier KAT2A presents a selective target in a subset of well-differentiated microsatellite-stable colorectal cancers","authors":"Vida Kufrin, Annika Seiler, Silke Brilloff, Helen Rothfuß, Sandra Küchler, Silvia Schäfer, Elahe Rahimian, Jonas Baumgarten, Li Ding, Frank Buchholz, Claudia R. Ball, Martin Bornhäuser, Hanno Glimm, Marius Bill, Alexander A. Wurm","doi":"10.1038/s41418-025-01479-7","DOIUrl":"https://doi.org/10.1038/s41418-025-01479-7","url":null,"abstract":"<p>Lysine acetyltransferase 2 A (KAT2A) plays a pivotal role in epigenetic gene regulation across various types of cancer. In colorectal cancer (CRC), increased <i>KAT2A</i> expression is associated with a more aggressive phenotype. Our study aims to elucidate the molecular underpinnings of <i>KAT2A</i> dependency in CRC and assess the consequences of <i>KAT2A</i> depletion. We conducted a comprehensive analysis by integrating CRISPR-Cas9 screening data with genomics, transcriptomics, and global acetylation patterns in CRC cell lines to pinpoint molecular markers indicative of <i>KAT2A</i> dependency. Additionally, we characterized the phenotypic effect of a CRISPR-interference-mediated <i>KAT2A</i> knockdown in CRC cell lines and patient-derived 3D spheroid cultures. Moreover, we assessed the effect of <i>KAT2A</i> depletion within a patient-derived xenograft mouse model in vivo. Our findings reveal that <i>KAT2A</i> dependency is closely associated with microsatellite stability, lower mutational burden, and increased molecular differentiation signatures in CRC, independent of the <i>KAT2A</i> expression levels. <i>KAT2A-</i>dependent CRC cells display higher gene expression levels and enriched H3K27ac marks at gene loci linked to enterocytic differentiation. Furthermore, loss of <i>KAT2A</i> leads to decreased cell growth and viability in vitro and in vivo, downregulation of proliferation- and stem cell-associated genes, and induction of differentiation markers. Altogether, our data show that a specific subset of CRCs with a more differentiated phenotype relies on KAT2A. For these CRC cases, KAT2A might represent a promising novel therapeutic target.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"57 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712973","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}

{"title":"SIRT7 regulates T-cell antitumor immunity through modulation BCAA and fatty acid metabolism","authors":"Zuojian Hu, Yingji Chen, Jielin Lei, Ke Wang, Ziyue Pan, Lei Zhang, Xiayun Xu, Wenhui Li, Lianjun Zhang, Xue Qin, Ronghua Liu, Yiwei Chu, Chenji Wang, Hongxiu Yu","doi":"10.1038/s41418-025-01490-y","DOIUrl":"https://doi.org/10.1038/s41418-025-01490-y","url":null,"abstract":"<p>SIRT7, one of the least studied members of the Sirtuins family, is an NAD⁺-dependent lysine deacetylase and desuccinylase. While previous studies using affinity enrichment and quantitative proteomics identified numerous lysine-deacetylated substrates of SIRT7, its lysine-desuccinylated substrates remain underexplored, limiting our understanding of its role in cellular homeostasis. Here, we demonstrated that SIRT7 is predominantly expressed in immune tissues, especially in adaptive immune cells, including T cells. Through proteomics, lysine succinylome, and acetylome analysis of spleen from wild-type (WT) and <i>Sirt7</i>^{<i>−/−</i>} mice, we identified significant succinylation of proteins involved in the branched-chain amino acid (BCAA) catabolism pathway in <i>Sirt7</i>^{<i>−/−</i>} mice. We further found that SIRT7 partially localizes to mitochondria, interacting with key enzymes of the BCAA catabolism pathway and promoting their desuccinylation. <i>Sirt7</i> deficiency leads to enhanced BCAA catabolism, accumulation of acyl-CoA, and increased fatty acid (FA) synthesis. As T cells rely heavily on amino acid metabolism for activation, differentiation, and function, we investigated the impact of SIRT7 using a T cell-specific <i>Sirt7</i> knockout mouse model (<i>Sirt7</i>^<i>fl/fl</i><i>Cd4</i>-Cre). Our results show that SIRT7 is crucial for T cell proliferation, activation, and antitumor function. <i>Sirt7</i> deficiency in T cells results in the accumulation of BCAA metabolites and FAs, reduced cytotoxic cytokines secretion such as IFN-γ, and T cell exhaustion. Reducing BCAA levels with BT2, a BCKDK inhibitor, or BCAA-free treatment alleviated these effects, while FA treatment exacerbates them. Overall, our findings identify SIRT7 as a critical regulator linking BCAA and FA metabolism to T cell antitumor immunity, providing new insights into its potential as a therapeutic target.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"33 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712974","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}

{"title":"ATOH8 confers the vulnerability of tumor cells to ferroptosis by repressing SCD expression","authors":"Huixiang Xiao, Xinxing Du, Huan Hou, Wenyun Guo, Zhenkeke Tao, Shijia Bao, Zhenzhen Wen, Nan Jing, Wei-Qiang Gao, Baijun Dong, Yu-Xiang Fang","doi":"10.1038/s41418-025-01482-y","DOIUrl":"https://doi.org/10.1038/s41418-025-01482-y","url":null,"abstract":"<p>Emerging evidence indicates that transcriptional regulation plays pivotal roles in modulating cellular vulnerability to ferroptosis. However, the intricate mechanisms governing these processes remain poorly understood. In this study, we identify ATOH8, a basic helix-loop-helix (bHLH) transcription factor, as a key player in ferroptosis regulation. ATOH8 is significantly upregulated in tumor cells following treatment with a ferroptosis inducer. Overexpression of ATOH8 increases the susceptibility of tumor cells to ferroptosis, while deletion of ATOH8 promotes ferroptosis evasion. Mechanistically, ATOH8 confers the sensitivity of tumor cells to ferroptosis by suppressing the transcription of stearoyl-CoA desaturase (SCD). Additionally, another bHLH family member, TCF3, is found to functions as a co-factor with ATOH8 by forming a TCF3-ATOH8 transcriptional repressive complex that suppresses SCD transcription. Furthermore, searching for upstream element reveals that EZH2 epigenetically suppresses ATOH8 expression by promoting DNA methylation in the ATOH8 promoter region and increasing the level of H3K27 me3. Importantly, pharmacological inhibition of EZH2 in a combined with a ferroptosis inducer markedly impedes tumor growth both in vitro and in vivo. Collectively, our study elucidates a molecular link between ferroptosis and epigenetic and transcriptional regulation, highlighting the potential of EZH2 and ATOH8 as therapeutic targets for cancer treatment.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"21 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703189","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}

{"title":"TRIM21-driven K63-linked ubiquitination of RBM38c, as a novel interactor of BECN1, contributes to DNA damage-induced autophagy","authors":"Lishenglan Xia, Yusheng Xing, Xinjia Ye, Yuanshun Wu, Ying Yang, Ziyi Yin, Anni Wang, Jian Chen, Min Zhang","doi":"10.1038/s41418-025-01480-0","DOIUrl":"https://doi.org/10.1038/s41418-025-01480-0","url":null,"abstract":"<p>Autophagy is essential in DNA damage response by limiting damage, but its responsive activation remains unclear. RBM38 (RBM38a), an RNA-binding protein, regulates mRNA metabolism and plays a key role in controlling cell cycle progression, senescence, and cancer. In this study, we uncovered a novel primate-specific isoform, RBM38c, with 32 extra amino acids from exon 2, which imparts a distinct capacity to promote autophagy upon DNA damage. TP53 increases RBM38c expression upon DNA damage, while TRIM21 facilitates its K63-linked ubiquitination at lysine (K) 35. Activated RBM38c enhances its interaction with BECN1, promoting the formation of the ATG14-containing PtdIns3K-C1 complex and thus autophagy initiation. A K35R mutation or TRIM21 deficiency impairs RBM38c ubiquitination, preventing autophagy activation upon DNA damage. Moreover, RBM38c-driven autophagy protects cells from DNA damage-induced apoptosis and promotes survival, with this beneficial effect susceptible to suppression by the autophagy inhibitor 3-methyladenine. Consequently, depleting RBM38c enhances the efficacy of DNA-damaging drugs by impairing autophagy and increasing DNA damage. Clinical lung cancer samples show a positive correlation between RBM38c expression and LC3 expression, and this correlation is linked to chemotherapy resistance. Together, our study reveals a novel mechanism for DNA damage-induced autophagy, involving K63-linked ubiquitination of RBM38c as a critical interactor with BECN1.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"41 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143703191","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}

{"title":"NAT10-mediated N4-acetylcytidine modification in KLF9 mRNA promotes adipogenesis","authors":"Xinxing Wan, Linghao Wang, Md Asaduzzaman Khan, Lin Peng, Xiaoying Sun, Xuan Yi, Zhouqi Wang, Ke Chen","doi":"10.1038/s41418-025-01483-x","DOIUrl":"https://doi.org/10.1038/s41418-025-01483-x","url":null,"abstract":"<p>Dysfunctional adipogenesis is a major contributor of obesity. N-acetyltransferase 10 (NAT10) plays a crucial role in regulating N4-acetylcysteine (ac4C) modification in tRNA, 18SrRNA, and mRNA. As the sole “writer” in the ac4C modification process, NAT10 enhances mRNA stability and translation efficiency. There are few reports on the relationship between NAT10 and adipogenesis, as well as obesity. Our study revealed a significant upregulation of NAT10 in adipose tissues of obese individuals and high-fat diet-fed mice. Furthermore, our findings revealed that the overexpression of NAT10 promotes adipogenesis, while its silencing inhibits adipogenesis in both human adipose tissue-derived stem cells (hADSCs) and 3T3-L1 cells. These results indicate the intimate relationship between NAT10 and obesity. After silencing mouse NAT10 (mNAT10), we identified 30 genes that exhibited both hypo-ac4C modification and downregulation in their expression, utilizing a combined approach of acRIP-sequencing (acRIP-seq) and RNA-sequencing (RNA-seq). Among these genes, we validated KLF9 as a target of NAT10 through acRIP-PCR. KLF9, a pivotal transcription factor that positively regulates adipogenesis. Our findings showed that NAT10 enhances the stability of KLF9 mRNA and further activates the CEBPA/B-PPARG pathway. Furthermore, a dual-luciferase reporter assay demonstrated that NAT10 can bind to three motifs of mouse KLF9 and one motif of human KLF9. In vivo studies revealed that adipose tissue-targeted mouse AAV-NAT10 (AAV-shRNA-mNAT10) inhibits adipose tissue expansion in mice. Additionally, Remodelin, a specific NAT10 inhibitor, significantly reduced body weight, adipocyte size, and adipose tissue expansion in high-fat diet-fed mice by inhibiting KLF9 mRNA ac4C modification. These findings provide novel insights and experimental evidence of the prevention and treatment of obesity, highlighting NAT10 and its downstream targets as potential therapeutic targets.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"27 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675230","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}

{"title":"Cryo-EM structure of the brine shrimp mitochondrial ATP synthase suggests an inactivation mechanism for the ATP synthase leak channel","authors":"Amrendra Kumar, Juliana da Fonseca Rezende e Mello, Yangyu Wu, Daniel Morris, Ikram Mezghani, Erin Smith, Stephane Rombauts, Peter Bossier, Juno Krahn, Fred J. Sigworth, Nelli Mnatsakanyan","doi":"10.1038/s41418-025-01476-w","DOIUrl":"https://doi.org/10.1038/s41418-025-01476-w","url":null,"abstract":"<p>Mammalian mitochondria undergo Ca²⁺-induced and cyclosporinA (CsA)-regulated permeability transition (mPT) by activating the mitochondrial permeability transition pore (mPTP) situated in mitochondrial inner membranes. Ca²⁺-induced prolonged openings of mPTP under certain pathological conditions result in mitochondrial swelling and rupture of the outer membrane, leading to mitochondrial dysfunction and cell death. While the exact molecular composition and structure of mPTP remain unknown, mammalian ATP synthase was reported to form voltage and Ca²⁺-activated leak channels involved in mPT. Unlike in mammals, mitochondria of the crustacean <i>Artemia franciscana</i> have the ability to accumulate large amounts of Ca²⁺ without undergoing the mPT. Here, we performed structural and functional analysis of <i>A. franciscana</i> ATP synthase to study the molecular mechanism of mPTP inhibition in this organism. We found that the channel formed by the <i>A. franciscana</i> ATP synthase dwells predominantly in its inactive state and is insensitive to Ca²⁺, in contrast to porcine heart ATP synthase. Single-particle cryo-electron microscopy (cryo-EM) analysis revealed distinct structural features in <i>A. franciscana</i> ATP synthase compared with mammals. The stronger density of the e-subunit C-terminal region and its enhanced interaction with the c-ring were found in <i>A. franciscana</i> ATP synthase. These data suggest an inactivation mechanism of the ATP synthase leak channel and its possible contribution to the lack of mPT in this organism.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"56 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661412","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}

{"title":"Correction to: Hsp27 silencing coordinately inhibits proliferation and promotes Fas-induced apoptosis by regulating the PEA-15 molecular switch.","authors":"N Hayashi, J W Peacock, E Beraldi, A Zoubeidi, M E Gleave, C J Ong","doi":"10.1038/s41418-025-01478-8","DOIUrl":"https://doi.org/10.1038/s41418-025-01478-8","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646895","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}

{"title":"Neutralization of acyl CoA binding protein (ACBP) for the experimental treatment of osteoarthritis","authors":"Uxía Nogueira-Recalde, Flavia Lambertucci, Léa Montégut, Omar Motiño, Hui Chen, Sylvie Lachkar, Gerasimos Anagnostopoulos, Gautier Stoll, Sijing Li, Vincent Carbonier, Ester Saavedra Díaz, Francisco J. Blanco, Geert van Tetering, Mark de Boer, Maria Chiara Maiuri, Beatriz Caramés, Isabelle Martins, Guido Kroemer","doi":"10.1038/s41418-025-01474-y","DOIUrl":"https://doi.org/10.1038/s41418-025-01474-y","url":null,"abstract":"<p>The plasma concentrations of acyl CoA binding protein (ACBP) encoded by the gene <i>diazepam binding inhibitor</i> (<i>DBI</i>) are increased in patients with severe osteoarthritis (OA). Here, we show that knee OA induces a surge in plasma ACBP/DBI in mice subjected to surgical destabilization of one hind limb. Knockout of the <i>Dbi</i> gene or intraperitoneal (i.p.) injection of a monoclonal antibody (mAb) neutralizing ACBP/DBI attenuates OA progression in this model, supporting a pathogenic role for ACBP/DBI in OA. Furthermore, anti-ACBP/DBI mAb was also effective against OA after its intraarticular (i.a.) injection, as monitored by sonography, revealing the capacity of ACBP/DBI to locally reduce knee inflammation over time. In addition, i.a. anti-ACBP/DBI mAb improved functional outcomes, as indicated by the reduced weight imbalance caused by OA. At the anatomopathological level, i.a. anti-ACBP/DBI mAb mitigated histological signs of joint destruction and synovial inflammation. Of note, i.a. anti-ACBP/DBI mAb blunted the OA-induced surge of plasma ACBP/DBI, as well as that of other inflammatory factors including interleukin-1α, interleukin-33, and tumor necrosis factor. These findings are potentially translatable to OA patients because joints from OA patients express both ACBP/DBI and its receptor GABA_ARγ2. Moreover, a novel mAb against ACBP/DBI recognizing an epitope conserved between human and mouse ACBP/DBI demonstrated similar efficacy in mitigating OA as an anti-mouse ACBP/DBI-only mAb. In conclusion, ACBP/DBI might constitute a promising therapeutic target for the treatment of OA.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"49 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618716","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}

{"title":"PRDM16 deficiency promotes podocyte injury by impairing insulin receptor signaling","authors":"Qian Yuan, Ben Tang, Yaru Xie, Yajuan Xie, Yuting Zhu, Hua Su, Youhua Liu, Chun Zhang","doi":"10.1038/s41418-025-01477-9","DOIUrl":"https://doi.org/10.1038/s41418-025-01477-9","url":null,"abstract":"<p>Impaired glucose uptake regulated by suppressed insulin receptor signaling is a key driving force of podocytopathies. The identification of potential therapeutic targets that mediate podocyte insulin receptor signaling holds significant clinical importance. Here, we observed a substantial reduction in PR domain-containing 16 (PRDM16) expression within damaged podocytes in both humans and mice. Podocyte-specific <i>Prdm16</i> deletion aggravated podocyte injury, albuminuria, and glomerulosclerosis in diabetic nephropathy (DN) mice. Conversely, exogenous PRDM16 delivered by lentivirus mitigated these pathological changes in DN mice and adriamycin (ADR) nephropathy mice. Furthermore, we demonstrated that loss of PRDM16 blocked glucose uptake of podocytes by inhibiting insulin receptor signaling. Mechanistically, PRDM16 deficiency downregulated the transcription of NEDD4L, subsequently enhancing the stability of IKKβ protein. The accumulation of IKKβ caused by the loss of PRDM16 led to the phosphorylation of serine residues on insulin receptor substrate-1 (IRS-1), thereby promoting IRS-1 degradation. Exogenous NEDD4L mitigated podocyte injury induced by PRDM16 knockdown in vitro and attenuated ADR nephropathy in vivo. Our study clarified the role and mechanism of PRDM16 in insulin receptor signaling and podocyte injury, providing a potential therapeutic target for podocytopathies.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"38 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589635","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}

{"title":"CKLF1 disrupts microglial efferocytosis following acute ischemic stroke by binding to phosphatidylserine","authors":"Ping-long Fan, Hua-qing Lai, Hong-yun Wang, Kai-chao Hu, Yuan Ruan, Jun-rui Ye, Sha-sha Wang, Ye Peng, Wen-bin He, Gang Li, Xu Yan, Shi-feng Chu, Zhao Zhang, Nai-hong Chen","doi":"10.1038/s41418-025-01475-x","DOIUrl":"https://doi.org/10.1038/s41418-025-01475-x","url":null,"abstract":"<p>Efferocytosis is crucial for the clearance of apoptotic cells (ACs) following acute ischemic stroke (AIS), however, its mechanism remains unclear. This study reveals that chemokine-like factor 1 (CKLF1) disrupts efferocytosis by promoting AC finding and internalization while impairing AC degradation in microglia. CKLF1 deficiency reduced the proportion of ACs and lowered levels of damage-associated molecular patterns. Mechanistically, CKLF1 binds to phosphatidylserine on apoptotic neurons/blebs, recruiting microglia to the ischemic penumbra via a C-C chemokine receptor 4 (CCR4)-dependent pathway. Apoptotic blebs with CKLF1 are engulfed into microglia, triggering the rapid production of interleukin-6 (IL6). IL6 enhances AC internalization through the signal transducer and activator of transcription 3 (STAT3)-vav guanine nucleotide exchange factor 1 (VAV1)-ras-related C3 botulinum toxin substrate 1 (RAC1) signaling cascade but simultaneously inhibits transcription factor EB (TFEB) nuclear translocation, leading to lysosomal dysfunction. This effect results in AC accumulation, compromising microglial efferocytosis efficiency and integrity. These findings uncover a novel regulatory axis induced by CKLF1, emphasizing the complex balance between AC internalization and degradation in microglial efferocytosis.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"68 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143576248","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}