Cell reportsPub Date : 2025-04-01DOI: 10.1016/j.celrep.2025.115493
Yangdian Lai, Xiaoxu Yang, Dong Wei, Xin Wang, Ruiming Sun, Yunfei Li, Ping Ji, Yujie Bao, Tiancheng Chu, Chenxing Zhang, Qiming Liang, Jie Xu, Xinxin Zhang, Yingying Chen, Ying Wang
{"title":"BCG-trained macrophages couple LDLR upregulation to type I IFN responses and antiviral immunity.","authors":"Yangdian Lai, Xiaoxu Yang, Dong Wei, Xin Wang, Ruiming Sun, Yunfei Li, Ping Ji, Yujie Bao, Tiancheng Chu, Chenxing Zhang, Qiming Liang, Jie Xu, Xinxin Zhang, Yingying Chen, Ying Wang","doi":"10.1016/j.celrep.2025.115493","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115493","url":null,"abstract":"<p><p>Trained immunity refers to memory-like responses of innate immune cells when they re-encounter pathogenic stimuli. Bacillus Calmette-Guérin (BCG) vaccination implies enhanced antiviral immunity, whereas the underlying mechanisms remain unclear. Herein, we have uncovered elevated expression of low-density lipoprotein receptor (LDLR) on BCG-trained macrophages with robust type I interferon (IFNI) production and antiviral effects both in vivo and in vitro. Consequently, cholesterol is accumulated in BCG-trained macrophages, leading to the augmentation of NFE2L1 expression and the formation of NFE2L1/IRAK1/TRIM25 complex where TRIM25 mediates IRAK1 K63 polyubiquitination to exaggerate IFNI responses in an RIG-I-dependent manner. We have also observed LDLR<sup>+</sup> macrophages displaying heightened IFNI responses in BCG-treated human macrophages. To antagonize LDLR degradation by PCSK9 inhibitors increases IFNI responses in the macrophages and accelerated viral clearance. Our study thus couples LDLR upregulation to antiviral activity in BCG-trained macrophages, making commercial PCSK9 inhibitors potential antiviral indications in clinic.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 4","pages":"115493"},"PeriodicalIF":7.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779258","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}
Cell reportsPub Date : 2025-04-01DOI: 10.1016/j.celrep.2025.115487
Wen-Juan Li, Yan-Chao Chen, Yi-An Lin, Yi-Qin Zou, Guo-Sheng Hu, Jing-Jing Yang, Xin-Yu Nie, Mei-Yan Li, Yi-Ran Wang, Yao-Hui He, Yan Zhao, Yu-Hua Tan, Xianming Deng, Wei-Ling He, Yan Cheng, Fang-Meng Fu, Wen Liu
{"title":"Hypoxia-induced PRMT1 methylates HIF2β to promote breast tumorigenesis via enhancing glycolytic gene transcription.","authors":"Wen-Juan Li, Yan-Chao Chen, Yi-An Lin, Yi-Qin Zou, Guo-Sheng Hu, Jing-Jing Yang, Xin-Yu Nie, Mei-Yan Li, Yi-Ran Wang, Yao-Hui He, Yan Zhao, Yu-Hua Tan, Xianming Deng, Wei-Ling He, Yan Cheng, Fang-Meng Fu, Wen Liu","doi":"10.1016/j.celrep.2025.115487","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115487","url":null,"abstract":"<p><p>Hypoxia-induced metabolic reprogramming is closely linked to breast cancer progression. Through transcriptomic analysis, we identified PRMT1 as a direct target of hypoxia-inducible factor 1α (HIF1α) under hypoxic conditions in breast cancer cells. In turn, PRMT1 enhances the expression of HIF1α-driven glycolytic genes. Mechanistically, PRMT1 methylates HIF2β at arginine 42, facilitating the formation, chromatin binding, and the transcriptional activity of the HIF1α/HIF2β heterodimer. Genetic and pharmacological inhibition of PRMT1 suppresses HIF2β methylation, HIF1α/HIF2β heterodimer formation, chromatin binding, glycolytic gene expression, lactate production, and the malignant behaviors of breast cancer cells. Moreover, combination treatment with iPRMT1, a PRMT1 inhibitor, and menadione, an HIF1α/P300 interaction inhibitor, demonstrates synergistic effects in suppressing breast tumor growth. Clinically, PRMT1 and PRMT1-mediated HIF2β methylation were significantly elevated in breast tumors compared with adjacent normal tissues. In conclusion, our findings reveal the critical role of PRMT1-mediated arginine methylation in glycolytic gene expression, metabolic reprogramming, and breast tumor growth.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 4","pages":"115487"},"PeriodicalIF":7.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771380","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}
Cell reportsPub Date : 2025-04-01DOI: 10.1016/j.celrep.2025.115498
Luis M Molinos-Albert, Rocío Rubio, Carla Martín-Pérez, Edwards Pradenas, Cèlia Torres, Alfons Jiménez, Mar Canyelles, Marta Vidal, Diana Barrios, Silvia Marfil, Ester Aparicio, Anna Ramírez-Morros, Benjamin Trinité, Josep Vidal-Alaball, Pere Santamaria, Pau Serra, Luis Izquierdo, Ruth Aguilar, Anna Ruiz-Comellas, Julià Blanco, Carlota Dobaño, Gemma Moncunill
{"title":"Long-lasting antibody B-cell responses to SARS-CoV-2 three years after the onset of the pandemic.","authors":"Luis M Molinos-Albert, Rocío Rubio, Carla Martín-Pérez, Edwards Pradenas, Cèlia Torres, Alfons Jiménez, Mar Canyelles, Marta Vidal, Diana Barrios, Silvia Marfil, Ester Aparicio, Anna Ramírez-Morros, Benjamin Trinité, Josep Vidal-Alaball, Pere Santamaria, Pau Serra, Luis Izquierdo, Ruth Aguilar, Anna Ruiz-Comellas, Julià Blanco, Carlota Dobaño, Gemma Moncunill","doi":"10.1016/j.celrep.2025.115498","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115498","url":null,"abstract":"<p><p>Immune memory is essential for the effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. In the current context of the pandemic, with a diminished vaccine efficacy against emerging variants, it remains crucial to perform long-term studies to evaluate the durability and quality of immune responses. Here, we examined the antibody and memory B-cell responses in a cohort of 113 healthcare workers with distinct exposure histories over a 3-year period. Previously infected and naive participants developed comparable humoral responses by 17 months after receiving a full three-dose mRNA vaccination. In addition, both maintained a substantial SARS-CoV-2-reactive memory B-cell pool, associated with a lower incidence of breakthrough infections in naive participants. Of note, previously infected participants developed an expanded SARS-CoV-2-reactive CD27<sup>-</sup>CD21<sup>-</sup> atypical B-cell population that remained stable throughout the follow-up period. Thus, previous SARS-CoV-2 infection differentially imprints the memory B-cell compartment without compromising the development of long-lasting humoral responses.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 4","pages":"115498"},"PeriodicalIF":7.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771384","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}
Cell reportsPub Date : 2025-04-01DOI: 10.1016/j.celrep.2025.115523
Wen Li, Dan Su, Xining Li, Kang Lu, Qingpei Huang, Jiajun Zheng, Xiaopeng Luo, Gong Chen, Xiaoying Fan
{"title":"Identification of the core regulatory program driving NEUROD1-induced neuronal reprogramming.","authors":"Wen Li, Dan Su, Xining Li, Kang Lu, Qingpei Huang, Jiajun Zheng, Xiaopeng Luo, Gong Chen, Xiaoying Fan","doi":"10.1016/j.celrep.2025.115523","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115523","url":null,"abstract":"<p><p>NEUROD1 (ND1)-induced astrocyte-to-neuron (AtN) conversion shows promise for treating neurological disorders. To gain insight into the molecular mechanisms of neuronal reprogramming, we established an in vitro system using primary cortical astrocyte cultures from postnatal rats and employed single-cell and multiomics sequencing. Our findings indicate that the initial cultures primarily consisted of immature astrocytes (ImAs), with potentially a minor presence of radial glial cells. The ImAs initially went through an intermediate state, activating both astrocyte and neural progenitor genes. Subsequently, they mimic in vivo neurogenesis to acquire mature neuronal characteristics. We show that ND1 acted as a pioneer factor that reshapes the chromatin landscape of astrocytes to that of neurons. This restructuring promotes the expression of neurogenic genes via inducing H3K27ac modification. Through integrative analysis of various ND1-induced neuronal specification systems, we identified 25 ND1 targets, including Hes6, as key regulators. Thus, our work highlights the key role of ND1 and its downstream regulators in neuronal reprogramming.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 4","pages":"115523"},"PeriodicalIF":7.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771383","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":"SOSTDC1 downregulation in CD4<sup>+</sup> T cells confers protection against obesity-induced insulin resistance.","authors":"Dehai Li, Jing Zhu, Mingyue Zhang, Qiping Shi, Rong Guo, Daming Zhang, Pei Zheng, Hua Zhang, Guangqiang Li, Jie Wu, Guodong Sun, Qiong Wen, Jingyi Tan, Zonghua Liu, Xindong Liu, Hengwen Yang, Hongyun Lu, Guangchao Cao, Zhinan Yin, Qian Wang","doi":"10.1016/j.celrep.2025.115496","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115496","url":null,"abstract":"<p><p>Adipose-resident T cells play a crucial role in the development of obesity-induced insulin resistance. However, the specific mechanisms, particularly those involving non-immune cytokines, remain unclear. Here, we report significantly elevated levels of sclerostin domain-containing protein 1 (SOSTDC1) in individuals with type 2 diabetes (T2D), showing positive correlations with fasting glucose and HbA1c. T cell-specific Sostdc1-deficient mice exhibit resistance to age-induced adipose lipid accumulation and glucose dysregulation at 12 months and protect against obesity-induced insulin resistance without affecting proinflammatory macrophage infiltration or adipose inflammation. Mechanistically, SOSTDC1 disrupts the lipid balance in adipocytes by promoting lipogenesis and inhibiting lipolysis through the LRP5/6-β-catenin pathway. Furthermore, T cell receptor (TCR) signaling significantly amplifies SOSTDC1 secretion in CD4<sup>+</sup> T cells. In summary, our study uncovers an additional mechanism by which T cells contribute to obesity and insulin resistance, suggesting that inhibiting SOSTDC1 could be a promising immunotherapeutic strategy for metabolic disorders.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 4","pages":"115496"},"PeriodicalIF":7.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771387","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":"Intestinal-region-specific functions of AHR in intrinsic enteric neurons during infections.","authors":"Zijia Sun, Yingsheng Wang, Shaorui Liu, Hui Li, Danyang He, Heping Xu","doi":"10.1016/j.celrep.2025.115524","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115524","url":null,"abstract":"<p><p>Intrinsic enteric neurons (iENs) form a crucial neuronal network within the myenteric and submucosal plexus of the gastrointestinal tract, primarily responsible for regulating gut peristalsis. The mechanisms by which iENs sense and integrate dietary and microbial signals to regulate intestinal homeostasis and inflammation remain unclear. Here, we showed that environmental sensor aryl hydrocarbon receptor (AHR) was expressed in different iEN subsets in the ileum and colon and that AHR ligands differentially modulated iEN activity in these regions. Genetic perturbation of Ahr in neurons increased iEN activation in the ileum but, conversely, decreased it in the colon in response to different intestinal pathogens. Furthermore, neuronal AHR deficiency enhanced the clearance of bacterial pathogens, which was associated with increased proliferation and abundance of group 3 innate lymphoid cells in the ileum. Together, our findings demonstrate the region-specific functions of AHR in neurons in response to infections.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 4","pages":"115524"},"PeriodicalIF":7.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779267","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}
Cell reportsPub Date : 2025-03-30DOI: 10.1016/j.celrep.2025.115457
Lingyun Zhou, Chang-Hai Liu, Duoduo Lv, Klarke Michael Sample, Ángela Rojas, Yugu Zhang, Huandi Qiu, Linye He, Li Zheng, Liyu Chen, Binru Cai, Yiguo Hu, Manuel Romero-Gómez
{"title":"Halting hepatocellular carcinoma: Identifying intercellular crosstalk in HBV-driven disease.","authors":"Lingyun Zhou, Chang-Hai Liu, Duoduo Lv, Klarke Michael Sample, Ángela Rojas, Yugu Zhang, Huandi Qiu, Linye He, Li Zheng, Liyu Chen, Binru Cai, Yiguo Hu, Manuel Romero-Gómez","doi":"10.1016/j.celrep.2025.115457","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115457","url":null,"abstract":"<p><p>Hepatitis B infection can lead to liver fibrosis and hepatocellular carcinoma (HCC). Despite antiviral therapies, some patients still develop HCC. This study investigates hepatitis B virus (HBV)-induced hepatocyte-hepatic stellate cell (HSC) crosstalk and its role in liver fibrosis and HCC. Using MYC-driven liver cancer stem cell organoids, HCC-patient-derived xenograft (PDX) models, and HBV replication models, this study reveals that HBV transcription affected hepatocyte development, activated the DNA repair pathway, and promoted glycolysis. HBV activated nicotinamide phosphoribosyltransferase (NAMPT) through DNA damage receptor ATR. NAMPT-insulin receptor (INSR)-mediated hepatocyte-HSC crosstalk caused HSCs to develop a myofibroblast phenotype and activated telomere maintenance mechanisms via PARP1 multisite lactylation. Inhibition of the ATR-NAMPT-INSR-PARP1 pathway effectively blocks HBV-induced liver fibrosis and HCC progression. Targeting this pathway could be a promising strategy for chronic HBV infection management.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 4","pages":"115457"},"PeriodicalIF":7.5,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751136","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}
Cell reportsPub Date : 2025-03-29DOI: 10.1016/j.celrep.2025.115492
Somnath Koley, Poonam Jyoti, Maneesh Lingwan, Michael Wei, Chunhui Xu, Kevin L Chu, Russell B Williams, Abraham J Koo, Jay J Thelen, Dong Xu, Doug K Allen
{"title":"Persistent fatty acid catabolism during plant oil synthesis.","authors":"Somnath Koley, Poonam Jyoti, Maneesh Lingwan, Michael Wei, Chunhui Xu, Kevin L Chu, Russell B Williams, Abraham J Koo, Jay J Thelen, Dong Xu, Doug K Allen","doi":"10.1016/j.celrep.2025.115492","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115492","url":null,"abstract":"<p><p>Plant lipids are an essential energy source for diets and are a sustainable alternative to petroleum-based fuels and feedstocks. Fatty acid breakdown during seed germination is crucial for seedling establishment but unexpected during seed filling. Here, we demonstrate that the simultaneous biosynthesis and degradation of fatty acids begins early and continues across all phases of oil filling and throughout the photoperiod. Tests in camelina, rapeseed, and an engineered high-oil tobacco line confirmed that concomitant synthesis and breakdown in oil-producing tissues over development is the rule rather than the exception. Furthermore, we show that transgenics, designed to elevate fatty acid biosynthesis, failed to achieve anticipated increases in storage lipid levels due to increased degradation, potentially explaining the underperformance of engineered lines compared to expectations more generally.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 4","pages":"115492"},"PeriodicalIF":7.5,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751210","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}
Cell reportsPub Date : 2025-03-29DOI: 10.1016/j.celrep.2025.115479
Yan Zhang, Guoying Zhang, Brittany Dong, Ankit Pandeya, Jian Cui, Samuel Dos Santos Valenca, Ling Yang, Jiaqian Qi, Zhuodong Chai, Congqing Wu, Daniel Kirchhofer, Toshihiko Shiroishi, Fadi Khasawneh, Min Tao, Feng Shao, Christopher M Waters, Yinan Wei, Zhenyu Li
{"title":"Pyroptosis of pulmonary fibroblasts and macrophages through NLRC4 inflammasome leads to acute respiratory failure.","authors":"Yan Zhang, Guoying Zhang, Brittany Dong, Ankit Pandeya, Jian Cui, Samuel Dos Santos Valenca, Ling Yang, Jiaqian Qi, Zhuodong Chai, Congqing Wu, Daniel Kirchhofer, Toshihiko Shiroishi, Fadi Khasawneh, Min Tao, Feng Shao, Christopher M Waters, Yinan Wei, Zhenyu Li","doi":"10.1016/j.celrep.2025.115479","DOIUrl":"10.1016/j.celrep.2025.115479","url":null,"abstract":"<p><p>The NAIP/NLRC4 inflammasome plays a pivotal role in the defense against bacterial infections, with its in vivo physiological function primarily recognized as driving inflammation in immune cells. Acute lung injury (ALI) is a leading cause of mortality in sepsis. In this study, we identify that the NAIP/NLRC4 inflammasome is highly expressed in both macrophages and pulmonary fibroblasts and that pyroptosis of these cells plays a critical role in lung injury. Mice challenged with gram-negative bacteria or flagellin developed lethal lung injury, characterized by reduced blood oxygen saturation, disrupted lung barrier function, and escalated inflammation. Flagellin-induced lung injury was protected in caspase-1 or GSDMD-deficient mice. These findings enhance our understanding of the NAIP/NLRC4 inflammasome's (patho)physiological function and highlight the significant role of inflammasome activation and pyroptosis in ALI during sepsis.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 4","pages":"115479"},"PeriodicalIF":7.5,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751248","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":"PRMT5-mediated methylation of METTL3 promotes cisplatin resistance in ovarian cancer by facilitating DNA repair mechanisms.","authors":"Qiaoxi Xia, Ronghui Zhong, Jingfang Zheng, Xiao Zhou, Xinwei Zhao, Sisi Wang, Botao Wang, Quanfeng Wu, Chen Xie, Beihua Kong, Qing Zhang, Tianzhi Huang","doi":"10.1016/j.celrep.2025.115484","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115484","url":null,"abstract":"<p><p>Cisplatin (CDDP) is a widely used chemotherapy drug for treating various solid tumors. However, resistance to CDDP significantly hampers patient outcomes. This study reveals that protein arginine methyltransferase (PRMT)5 methylates METTL3 at the R36 residue (METTL3-R36me2), which is crucial for CDDP resistance in ovarian cancer (OC) cells. Following CDDP exposure, MST4 is transactivated by nuclear factor-erythroid 2-related factor 2 (NRF2), a key regulator of antioxidant responses. MST4 stimulates PRMT5's methyltransferase activity and promotes its interaction with METTL3 via phosphorylation at Ser439 and Ser463, resulting in increased levels of METTL3-R36me2 and mRNA methylation at the N6 position of adenosine (m<sup>6</sup>A). The METTL3-R36me2 is recruited to DNA damage sites to promote RAD51 recruitment for homologous recombination (HR)-mediated double-strand break repair (DSBR) and enhance CDDP resistance. Importantly, targeting METTL3-R36me2 through inhibition of PRMT5 or METTL3 disrupts HR-DSBR and augments the cytotoxic effects of CDDP in ovarian tumor xenografts. Therefore, we conclude that METTL3-R36me2 represents a viable therapeutic target for overcoming CDDP resistance in OC.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 4","pages":"115484"},"PeriodicalIF":7.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751243","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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