Cell Death and Differentiation最新文献_第3页

AKAP1/PKA-mediated GRP75 phosphorylation at mitochondria-associated endoplasmic reticulum membranes protects cancer cells against ferroptosis AKAP1/PKA 介导的线粒体相关内质网膜上的 GRP75 磷酸化可保护癌细胞免受铁中毒的侵害

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2024-11-13 DOI: 10.1038/s41418-024-01414-2

Hao Liu, Shanliang Zheng, Guixue Hou, Junren Dai, Yanan Zhao, Fan Yang, Zhiyuan Xiang, Wenxin Zhang, Xingwen Wang, Yafan Gong, Li Li, Ning Zhang, Ying Hu

{"title":"AKAP1/PKA-mediated GRP75 phosphorylation at mitochondria-associated endoplasmic reticulum membranes protects cancer cells against ferroptosis","authors":"Hao Liu, Shanliang Zheng, Guixue Hou, Junren Dai, Yanan Zhao, Fan Yang, Zhiyuan Xiang, Wenxin Zhang, Xingwen Wang, Yafan Gong, Li Li, Ning Zhang, Ying Hu","doi":"10.1038/s41418-024-01414-2","DOIUrl":"https://doi.org/10.1038/s41418-024-01414-2","url":null,"abstract":"Emerging evidence suggests that signaling pathways can be spatially regulated to ensure rapid and efficient responses to dynamically changing local cues. Ferroptosis is a recently defined form of lipid peroxidation-driven cell death. Although the molecular mechanisms underlying ferroptosis are emerging, spatial aspects of its signaling remain largely unexplored. By analyzing a public database, we found that a mitochondrial chaperone protein, glucose-regulated protein 75 (GRP75), may have a previously undefined role in regulating ferroptosis. This was subsequently validated. Interestingly, under ferroptotic conditions, GRP75 translocated from mitochondria to mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) and the cytosol. Further mechanistic studies revealed a highly spatial regulation of GRP75-mediated antiferroptotic signaling. Under ferroptotic conditions, lipid peroxidation predominantly accumulated at the ER, which activated protein kinase A (PKA) in a cAMP-dependent manner. In particular, a signaling microdomain, the outer mitochondrial membrane protein A-kinase anchor protein 1 (AKAP1)-anchored PKA, phosphorylated GRP75 at S148 in MAMs. This caused GRP75 to be sequestered outside the mitochondria, where it competed with Nrf2 for Keap1 binding through a conserved high-affinity RGD-binding motif, ETGE. Nrf2 was then stabilized and activated, leading to the transcriptional activation of a panel of antiferroptotic genes. Blockade of the PKA/GRP75 axis dramatically increased the responses of cancer cells to ferroptosis both in vivo and in vitro. Our identification a localized signaling cascade involved in protecting cancer cells from ferroptosis broadens our understanding of cellular defense mechanisms against ferroptosis and also provides a new target axis (AKAP1/PKA/GRP75) to improve the responses of cancer cells to ferroptosis.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"56 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610142","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}

引用次数: 0

Physiological and pathological roles of the transcriptional kinases CDK12 and CDK13 in the central nervous system 转录激酶 CDK12 和 CDK13 在中枢神经系统中的生理和病理作用

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2024-11-12 DOI: 10.1038/s41418-024-01413-3

Consuelo Pitolli, Alberto Marini, Claudio Sette, Vittoria Pagliarini

{"title":"Physiological and pathological roles of the transcriptional kinases CDK12 and CDK13 in the central nervous system","authors":"Consuelo Pitolli, Alberto Marini, Claudio Sette, Vittoria Pagliarini","doi":"10.1038/s41418-024-01413-3","DOIUrl":"https://doi.org/10.1038/s41418-024-01413-3","url":null,"abstract":"The cyclin-dependent kinases 12 (CDK12) and 13 (CDK13) govern several steps of gene expression, including transcription, RNA processing and translation. The main target of CDK12/13 is the serine 2 residue of the carboxy-terminal domain of RNA polymerase II (RNAPII), thus influencing the directionality, elongation rate and processivity of the enzyme. The CDK12/13-dependent regulation of RNAPII activity influences the expression of selected target genes with important functional roles in the proliferation and viability of all eukaryotic cells. Neuronal cells are particularly affected by the loss of CDK12/13, as result of the high dependency of neuronal genes on RNAPII processivity for their expression. Deregulation of CDK12/13 activity strongly affects brain physiology by influencing the stemness potential and differentiation properties of neuronal precursor cells. Moreover, mounting evidence also suggest the involvement of CDK12/13 in brain tumours. Herein, we discuss the functional role(s) of CDK12 and CDK13 in gene expression regulation and highlight similarities and differences between these highly homologous kinases, with particular attention to their impact on brain physiology and pathology. Lastly, we provide an overview of CDK12/13 inhibitors and of their efficacy in brain tumours and other neoplastic diseases.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"22 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142600989","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}

引用次数: 0

Integrin β6/Annexin A2 axis triggers autophagy to orchestrate hepatocellular carcinoma radioresistance 整合素β6/附件素A2轴触发自噬，协调肝细胞癌的放射抗性

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2024-11-12 DOI: 10.1038/s41418-024-01411-5

Ying Gao, Guangyan Wei, Hua Yu, Shuping Li, Yuhao Tang, Xin Yue, Yong Chen, Meixiao Zhan, Jian Wu

{"title":"Integrin β6/Annexin A2 axis triggers autophagy to orchestrate hepatocellular carcinoma radioresistance","authors":"Ying Gao, Guangyan Wei, Hua Yu, Shuping Li, Yuhao Tang, Xin Yue, Yong Chen, Meixiao Zhan, Jian Wu","doi":"10.1038/s41418-024-01411-5","DOIUrl":"https://doi.org/10.1038/s41418-024-01411-5","url":null,"abstract":"Radiotherapy (RT) is one of the main therapies for hepatocellular carcinoma (HCC), but its effectiveness has been constrained due to the resistance effect of radiation. Thus, the factors involved in radioresistance are evaluated and the underlying molecular mechanisms are also done. In this present study, we identified Integrin β6 (ITGB6) as a potential radioresistant gene through an integrative analysis of transcriptomic profiles, proteome datasets and survival using HCC cases treated with IR. We show that ITGB6 functionally contributed to radioresistance by activating autophagy through a series of in vitro and in vivo methods, such as clonogenic assays, autophagy flux (LC3B-GFP-mCherry reporter) analysis and a subcutaneous transplantation model. Mechanically, ITGB6 binds to Annexin A2 (ANXA2) and enhanced its stability by competitively antagonizing proteasome mediated ANXA2 degradation, thereby promoting autophagy and radioresistance. Notably, HCC radioresistance was significantly improved by either blocking ITGB6 or autophagy, but the combination was more effective. Importantly, ITGB6/ANXA2 axis triggered autophagic program endowed HCC cells with radioresistant activity in a radiated patient-derived xenograft (PDX) model and hydrodynamic injection in liver-specific Itgb6-knockout mice, further supported by clinical evidence. Together, our data revealed that ITGB6 is a radioresistant gene stabilizing the autophagy regulatory protein ANXA2, providing insights into the biological and potentially clinical significance of ITGB6/ANXA2 axis in radiotherapy planning of HCC.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"95 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601485","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}

引用次数: 0

hnRNPA2B1 deacetylation by SIRT6 restrains local transcription and safeguards genome stability SIRT6 对 hnRNPA2B1 的去乙酰化作用可抑制局部转录并保护基因组稳定性

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2024-11-07 DOI: 10.1038/s41418-024-01412-4

Feng Chen, Wenchao Xu, Ming Tang, Yuan Tian, Yuxin Shu, Xingkai He, Linmin Zhou, Qi Liu, Qian Zhu, Xiaopeng Lu, Jun Zhang, Wei-Guo Zhu

{"title":"hnRNPA2B1 deacetylation by SIRT6 restrains local transcription and safeguards genome stability","authors":"Feng Chen, Wenchao Xu, Ming Tang, Yuan Tian, Yuxin Shu, Xingkai He, Linmin Zhou, Qi Liu, Qian Zhu, Xiaopeng Lu, Jun Zhang, Wei-Guo Zhu","doi":"10.1038/s41418-024-01412-4","DOIUrl":"https://doi.org/10.1038/s41418-024-01412-4","url":null,"abstract":"Repair of double strand breaks (DSBs) by RNA-binding proteins (RBPs) is vital for ensuring genome integrity. DSB repair is accompanied by local transcriptional repression in the vicinity of transcriptionally active genes, but the mechanism by which RBPs regulate transcriptional regulation is unclear. Here, we demonstrated that RBP hnRNPA2B1 functions as a RNA polymerase-associated factor that stabilizes the transcription complex under physiological conditions. Following a DSB, hnRNPA2B1 is released from damaged chromatin, reducing the efficiency of RNAPII complex assembly, leading to local transcriptional repression. Mechanistically, SIRT6 deacetylates hnRNPA2B1 at K113/173 residues, enforcing its rapid detachment from DSBs. This process disrupts the integrity of the RNAPII complex on active chromatin, which is a pre-requisite for transient but complete repression of local transcription. Functionally, the overexpression of an acetylation mimic stabilizes the transcription complex and facilitates the functioning of the transcription machinery. hnRNPA2B1 acetylation status was negatively correlated with SIRT6 expression, and acetylation mimic enhanced radio-sensitivity in vivo. Our findings demonstrate that hnRNPA2B1 is crucial for transcriptional repression. We have uncovered the missing link between DSB repair and transcriptional regulation in genome stability maintenance, highlighting the potential of hnRNPA2B1 as a therapeutic target.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"13 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596851","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}

引用次数: 0

Correction: STAT3 dictates β-cell apoptosis by modulating PTEN in streptozocin-induced hyperglycemia 更正：STAT3 在链脲佐菌素诱导的高血糖中通过调节 PTEN 决定β细胞凋亡

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2024-11-07 DOI: 10.1038/s41418-024-01405-3

Qinjie Weng, Mengting Zhao, Jiahuan Zheng, Lijun Yang, Zijie Xu, Zhikang Zhang, Jincheng Wang, Jiajia Wang, Bo Yang, Q. Richard Lu, Meidan Ying, Qiaojun He

引用次数: 0

Localized release of muscle-generated BDNF regulates the initial formation of postsynaptic apparatus at neuromuscular synapses 肌肉产生的 BDNF 的局部释放调节神经肌肉突触后装置的初步形成

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2024-11-07 DOI: 10.1038/s41418-024-01404-4

Jinkai Zhang, Hiu-Lam Rachel Kwan, Chi Bun Chan, Chi Wai Lee

{"title":"Localized release of muscle-generated BDNF regulates the initial formation of postsynaptic apparatus at neuromuscular synapses","authors":"Jinkai Zhang, Hiu-Lam Rachel Kwan, Chi Bun Chan, Chi Wai Lee","doi":"10.1038/s41418-024-01404-4","DOIUrl":"https://doi.org/10.1038/s41418-024-01404-4","url":null,"abstract":"Growing evidence indicates that brain-derived neurotrophic factor (BDNF) is produced in contracting skeletal muscles and is secreted as a myokine that plays an important role in muscle metabolism. However, the involvement of muscle-generated BDNF and the regulation of its vesicular trafficking, localization, proteolytic processing, and spatially restricted release during the development of vertebrate neuromuscular junctions (NMJs) remain largely unknown. In this study, we first reported that BDNF is spatially associated with the actin-rich core domain of podosome-like structures (PLSs) at topologically complex acetylcholine receptor (AChR) clusters in cultured Xenopus muscle cells. The release of spatially localized BDNF is tightly controlled by activity-regulated mechanisms in a calcium-dependent manner. Live-cell time-lapse imaging further showed that BDNF-containing vesicles are transported to and captured at PLSs in both aneural and synaptic AChR clusters for spatially restricted release. Functionally, BDNF knockdown or furin-mediated endoproteolytic activity inhibition significantly suppresses aneural AChR cluster formation, which in turn affects synaptic AChR clustering induced by nerve innervation or agrin-coated beads. Lastly, skeletal muscle-specific BDNF knockout (MBKO) mice exhibit structural defects in the formation of aneural AChR clusters and their subsequent recruitment to nerve-induced synaptic AChR clusters during the initial stages of NMJ development in vivo. Together, this study demonstrated the regulatory roles of PLSs in the intracellular trafficking, spatial localization, and activity-dependent release of BDNF in muscle cells and revealed the involvement of muscle-generated BDNF and its proteolytic conversion in regulating the initial formation of aneural and synaptic AChR clusters during early NMJ development in vitro and in vivo.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"18 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594713","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}

引用次数: 0

Correction to: RIPK1 prevents TRADD-driven, but TNFR1 independent, apoptosis during development 更正为RIPK1 可防止发育过程中由 TRADD 驱动但独立于 TNFR1 的细胞凋亡。

IF 13.7 1区生物学

Cell Death and Differentiation Pub Date : 2024-11-07 DOI: 10.1038/s41418-024-01401-7

Holly Anderton, Esther Bandala-Sanchez, Daniel S. Simpson, James A. Rickard, Ashley P. Ng, Ladina Di Rago, Cathrine Hall, James E. Vince, John Silke, Gianmaria Liccardi, Rebecca Feltham

引用次数: 0

Tufm lactylation regulates neuronal apoptosis by modulating mitophagy in traumatic brain injury. Tufm 乳酰化通过调节创伤性脑损伤中的有丝分裂来调节神经细胞凋亡。

IF 13.7 1区生物学

Cell Death and Differentiation Pub Date : 2024-11-05 DOI: 10.1038/s41418-024-01408-0

Weiji Weng, Zhenghui He, Zixuan Ma, Jialin Huang, Yuhan Han, Qiyuan Feng, Wenlan Qi, Yidong Peng, Jiangchang Wang, Jiacheng Gu, Wenye Wang, Yong Lin, Gan Jiang, Jiyao Jiang, Junfeng Feng

{"title":"Tufm lactylation regulates neuronal apoptosis by modulating mitophagy in traumatic brain injury.","authors":"Weiji Weng, Zhenghui He, Zixuan Ma, Jialin Huang, Yuhan Han, Qiyuan Feng, Wenlan Qi, Yidong Peng, Jiangchang Wang, Jiacheng Gu, Wenye Wang, Yong Lin, Gan Jiang, Jiyao Jiang, Junfeng Feng","doi":"10.1038/s41418-024-01408-0","DOIUrl":"10.1038/s41418-024-01408-0","url":null,"abstract":"Lactates accumulation following traumatic brain injury (TBI) is detrimental. However, whether lactylation is triggered and involved in the deterioration of TBI remains unknown. Here, we first report that Tufm lactylation pathway induces neuronal apoptosis in TBI. Lactylation is found significantly increased in brain tissues from patients with TBI and mice with controlled cortical impact (CCI), and in neuronal injury cell models. Tufm, a key factor in mitophagy, is screened and identified to be mostly lactylated. Tufm is detected to be lactylated at K286 and the lactylation inhibits the interaction of Tufm and Tomm40 on mitochondria. The mitochondrial distribution of Tufm is then inhibited. Consequently, Tufm-mediated mitophagy is suppressed while mitochondria-induced neuronal apoptosis is increased. In contrast, the knockin of a lactylation-deficient TufmK286R mutant in mice rescues the mitochondrial distribution of Tufm and Tufm-mediated mitophagy, and improves functional outcome after CCI. Likewise, mild hypothermia, as a critical therapeutic method in neuroprotection, helps in downregulating Tufm lactylation, increasing Tufm-mediated mitophagy, mitigating neuronal apoptosis, and eventually ameliorating the outcome of TBI. A novel molecular mechanism in neuronal apoptosis, TBI-initiated Tufm lactylation suppressing mitophagy, is thus revealed.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575099","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}

引用次数: 0

The AKR1C1-CYP1B1-cAMP signaling axis controls tumorigenicity and ferroptosis susceptibility of extrahepatic cholangiocarcinoma. AKR1C1-CYP1B1-cAMP信号轴控制着肝外胆管癌的致瘤性和易感性。

IF 13.7 1区生物学

Cell Death and Differentiation Pub Date : 2024-10-30 DOI: 10.1038/s41418-024-01407-1

Chang Liu, Cheng Zhang, Hongkun Wu, Zhibin Zhao, Zhenhua Wang, Xiaomin Zhang, Jieli Yang, Wenlong Yu, Zhexiong Lian, Minghui Gao, Lin Zhou

{"title":"The AKR1C1-CYP1B1-cAMP signaling axis controls tumorigenicity and ferroptosis susceptibility of extrahepatic cholangiocarcinoma.","authors":"Chang Liu, Cheng Zhang, Hongkun Wu, Zhibin Zhao, Zhenhua Wang, Xiaomin Zhang, Jieli Yang, Wenlong Yu, Zhexiong Lian, Minghui Gao, Lin Zhou","doi":"10.1038/s41418-024-01407-1","DOIUrl":"https://doi.org/10.1038/s41418-024-01407-1","url":null,"abstract":"Extrahepatic cholangiocarcinoma (ECC), a highly malignant type of cancer with increasing incidence, has a poor prognosis due to limited treatment options. Based on genomic analysis of ECC patient samples, here we report that aldo-keto reductase family 1 member C1 (AKR1C1) is highly expressed in human ECC tissues and closely associated with ECC progression and poor prognosis. Intriguingly, we show that inducible AKR1C1 knockdown triggers ECC cells to undergo ferroptosis. Mechanistically, AKR1C1 degrades the protein stability of the cytochrome P450 family member CYP1B1, a newly discovered mediator of ferroptosis, via ubiquitin-proteasomal degradation. Additionally, AKR1C1 decreases CYP1B1 mRNA level through the transcriptional factor aryl-hydrocarbon receptor (AHR). Furthermore, the AKR1C1-CYP1B1 axis modulates ferroptosis in ECC cells via the cAMP-PKA signaling pathway. Finally, in a xenograft mouse model of ECC, AKR1C1 depletion sensitizes cancer cells to ferroptosis and synergizes with ferroptosis inducers to suppress tumor growth. Therefore, the AKR1C1-CYP1B1-cAMP signaling axis is a promising therapeutic target for ECC treatment, especially in combination with ferroptosis inducers.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544028","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}

引用次数: 0

METTL3 confers oxaliplatin resistance through the activation of G6PD-enhanced pentose phosphate pathway in hepatocellular carcinoma METTL3 通过激活肝细胞癌中 G6PD 增强的磷酸戊糖通路赋予奥沙利铂耐药性

IF 12.4 1区生物学

Cell Death and Differentiation Pub Date : 2024-10-29 DOI: 10.1038/s41418-024-01406-2

Xiaohan Jin, Yongrui Lv, Fengjie Bie, Jinling Duan, Chao Ma, Miaomiao Dai, Jiewei Chen, Lianghe Lu, Shuidan Xu, Jie Zhou, Si Li, Jiong Bi, Fengwei Wang, Dan Xie, Muyan Cai

{"title":"METTL3 confers oxaliplatin resistance through the activation of G6PD-enhanced pentose phosphate pathway in hepatocellular carcinoma","authors":"Xiaohan Jin, Yongrui Lv, Fengjie Bie, Jinling Duan, Chao Ma, Miaomiao Dai, Jiewei Chen, Lianghe Lu, Shuidan Xu, Jie Zhou, Si Li, Jiong Bi, Fengwei Wang, Dan Xie, Muyan Cai","doi":"10.1038/s41418-024-01406-2","DOIUrl":"https://doi.org/10.1038/s41418-024-01406-2","url":null,"abstract":"Oxaliplatin-based therapeutics is a widely used treatment approach for hepatocellular carcinoma (HCC) patients; however, drug resistance poses a significant clinical challenge. Epigenetic modifications have been implicated in the development of drug resistance. In our study, employing siRNA library screening, we identified that silencing the m6A writer METTL3 significantly enhanced the sensitivity to oxaliplatin in both in vivo and in vitro HCC models. Further investigations through combined RNA-seq and non-targeted metabolomics analysis revealed that silencing METTL3 impeded the pentose phosphate pathway (PPP), leading to a reduction in NADPH and nucleotide precursors. This disruption induced DNA damage, decreased DNA synthesis, and ultimately resulted in cell cycle arrest. Mechanistically, METTL3 was found to modify E3 ligase TRIM21 near the 3’UTR with N6-methyladenosine, leading to reduced RNA stability upon recognition by YTHDF2. TRIM21, in turn, facilitated the degradation of the rate-limiting enzyme of PPP, G6PD, through the ubiquitination-proteasome pathway. Importantly, high expression of METTL3 was significantly associated with adverse prognosis and oxaliplatin resistance in HCC patients. Notably, treatment with the specific METTL3 inhibitor, STM2457, significantly improved the efficacy of oxaliplatin. These findings underscore the critical role of the METTL3/TRIM21/G6PD axis in driving oxaliplatin resistance and present a promising strategy to overcome chemoresistance in HCC.<figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"23 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142536562","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}

引用次数: 0