Cell Death & Disease最新文献_第7页

Simvastatin suppresses spinal cord metastasis of medulloblastoma at clinically significant doses. 辛伐他汀在临床显著剂量下抑制髓母细胞瘤脊髓转移。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-15 DOI: 10.1038/s41419-025-07829-0

Charley Comer, Kian Cotton, Christopher Edwards, Xiaoyang Dai, Sara Badodi, Roberto Buccafusca, Chris Bennett, Andrew Peet, Alice Williams, David Michod, Elena Bochukova, Maria Victoria Niklison-Chirou

{"title":"Simvastatin suppresses spinal cord metastasis of medulloblastoma at clinically significant doses.","authors":"Charley Comer, Kian Cotton, Christopher Edwards, Xiaoyang Dai, Sara Badodi, Roberto Buccafusca, Chris Bennett, Andrew Peet, Alice Williams, David Michod, Elena Bochukova, Maria Victoria Niklison-Chirou","doi":"10.1038/s41419-025-07829-0","DOIUrl":"10.1038/s41419-025-07829-0","url":null,"abstract":"Medulloblastomas (MBs) are aggressive brain cancers and represent the most common primary malignant tumour in children. Current treatment protocols involve an intensive regimen of surgery, radiation therapy and chemotherapy, guided by histopathology and risk stratification. Unfortunately, disease relapse proves fatal in 30% of cases, and treatment efficacy is compromised as MB cells develop resistance. Therefore, there is a critical need for more effective and tolerable therapies, especially for the treatment of aggressive MBs associated with a poor prognosis. Lipid metabolism reprogramming, characterized by increased cholesterol synthesis, lipid uptake and the activation of de novo lipogenesis, is a newly identified hallmark of cancers. Cholesterol is an essential structural component of membranes that contributes to membrane integrity and fluidity. Recently, increasing evidence has indicated that cholesterol is a major determinant by modulating cell signalling events governing the hallmarks of cancer. Our research demonstrates there is an overexpression of cholesterol metabolism in group 3 (G3), and group 4 (G4) MB subgroups compared to Sonic Hedgehog (SHH)-MB subgroup. In these tumours, cholesterol metabolism supports cell migration through the Rho-GTPase signalling pathway. Notably, we observed that shifting the culture conditions from 2D to 3D significantly upregulates lipid metabolism. Furthermore, spheroids derived from G3/G4-MBs and SHH-MBs show similar sensitivity to low doses of simvastatin. We validated these findings in a xenograft mouse model, where treatment with low doses of simvastatin led to increased survival time and remarkably, also reduced the metastatic spread of MB cells to the spinal cord. These results suggest that simvastatin holds potential as an adjuvant treatment for patients with medulloblastoma.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"527"},"PeriodicalIF":8.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combining decitabine with radiotherapy to enhance nasopharyngeal carcinoma radiosensitivity via the TFAP2C-OTUD1-SLC25A11 axis. 地西他滨联合放疗通过TFAP2C-OTUD1-SLC25A11轴增强鼻咽癌放射敏感性

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-15 DOI: 10.1038/s41419-025-07858-9

Haixia Zhang, Siyang Liu, Dan Wang, Yaqi Liao, Shizhen Li, Jing He, Jie Shen, Lu Yan, Tengfei Xiao, Wangning Gu, Hongmin Yang, Hui Wang, Minghua Yang, Pan Chen

{"title":"Combining decitabine with radiotherapy to enhance nasopharyngeal carcinoma radiosensitivity via the TFAP2C-OTUD1-SLC25A11 axis.","authors":"Haixia Zhang, Siyang Liu, Dan Wang, Yaqi Liao, Shizhen Li, Jing He, Jie Shen, Lu Yan, Tengfei Xiao, Wangning Gu, Hongmin Yang, Hui Wang, Minghua Yang, Pan Chen","doi":"10.1038/s41419-025-07858-9","DOIUrl":"10.1038/s41419-025-07858-9","url":null,"abstract":"Nasopharyngeal carcinoma (NPC) is a common malignancy in certain geographic regions, with radiotherapy serving as the primary treatment. Recent research shows that epigenetics and deubiquitinases (DUBs) are crucial in NPC progression and treatment response. However, the emergence of radioresistance in NPC cells presents a significant challenge, often resulting in treatment failure. This study focuses on understanding the role of OTUD1 and methylation in NPC radiosensitivity and their mechanisms. In this study, OTUD1 and TFAP2C expression were significantly reduced in radioresistant NPC cell lines, likely due to the high methylation of TFAP2C. OTUD1 is significantly downregulated in radioresistant NPC, and its low expression is associated with enhanced radioresistance both in vitro and in vivo. Mechanistically, OTUD1 enhances NPC radiosensitivity by deubiquitinating and stabilizing SLC25A11, leading to increased Reactive oxygen species (ROS) and apoptosis. Clinically, low OTUD1 and SLC25A11 expression is associated with poor radiotherapy response and survival outcomes. Furthermore, we demonstrate that combining the methylation inhibitor Decitabine (DAC) with radiotherapy significantly improves treatment efficacy by overcoming radioresistance. These findings provide insights into NPC radioresistance and suggest that using DAC in combination with radiotherapy to target the TFAP2C-OTUD1-SLC25A11 axis could be a promising strategy to overcome radioresistance.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"525"},"PeriodicalIF":8.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeted delivery of the PKMYT1 inhibitor RP-6306 mediates PANoptosis in pancreatic cancer via mitotic catastrophe. 靶向递送PKMYT1抑制剂RP-6306通过有丝分裂突变介导胰腺癌PANoptosis。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-15 DOI: 10.1038/s41419-025-07835-2

Jingyun Chen, Jianghao Ren, Chaolei Zhang, Yang Lv, Jingbin Zhou, Weiliang Jiang, Chaojie Huang, Liping Cao

{"title":"Targeted delivery of the PKMYT1 inhibitor RP-6306 mediates PANoptosis in pancreatic cancer via mitotic catastrophe.","authors":"Jingyun Chen, Jianghao Ren, Chaolei Zhang, Yang Lv, Jingbin Zhou, Weiliang Jiang, Chaojie Huang, Liping Cao","doi":"10.1038/s41419-025-07835-2","DOIUrl":"10.1038/s41419-025-07835-2","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor often diagnosed in advanced stages due to its subtle early symptoms, making surgical options nonviable and requiring systemic chemotherapy. Current treatments mainly utilize gemcitabine, which provides limited efficacy. PKMYT1, a serine/threonine protein kinase crucial for cell cycle regulation, is overexpressed in PDAC and correlates with poor prognosis. Treatment with the PKMYT1 inhibitor RP-6306 promotes rapid mitotic entry, resulting in DNA damage and mitotic catastrophe, thereby inducing PANoptosis. RP-6306 effectively inhibits PDAC growth in vitro and in vivo, and shows enhanced anti-tumor activity when combined with gemcitabine, also reducing metastasis. However, gemcitabine has notable systemic toxicity. To target cancer cells more specifically, we utilized vesicles derived from cell membranes (BxPC-3M) to deliver a combination of RP-6306 and gemcitabine (GEM + RP-6306@BxPC-3M). This formulation effectively targets homotypic tumor cells and significantly inhibits tumor growth both in vitro and in vivo. These findings highlight the role of RP-6306 in inducing PANoptosis, characterize PANoptosis as a novel form of cell death associated with mitotic catastrophe, and confirm the synergistic antitumor activity of RP-6306 and gemcitabine in PDAC. Moreover, GEM + RP-6306@BxPC-3M exhibits improved safety and enhanced antitumor efficacy.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"526"},"PeriodicalIF":8.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Anoikis resistance in gastric cancer: a comprehensive review. 胃癌耐药研究综述

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-15 DOI: 10.1038/s41419-025-07860-1

Teresa D'Amore, Daniele Bravoco, Giuseppina Di Paola, Francesco Albano, Mariarita Brancaccio, Claudia Sabato, Giuseppe Cesta, Cinzia Zolfanelli, Vincenzo Lauciello, Geppino Falco, Pellegrino Mazzone

{"title":"Anoikis resistance in gastric cancer: a comprehensive review.","authors":"Teresa D'Amore, Daniele Bravoco, Giuseppina Di Paola, Francesco Albano, Mariarita Brancaccio, Claudia Sabato, Giuseppe Cesta, Cinzia Zolfanelli, Vincenzo Lauciello, Geppino Falco, Pellegrino Mazzone","doi":"10.1038/s41419-025-07860-1","DOIUrl":"10.1038/s41419-025-07860-1","url":null,"abstract":"Gastric cancer (GC) is a predominant malignant neoplasia responsible for cancer death worldwide. Because of the difficulty in early diagnosis as well as its high metastasis rate, GC shows an increasing incidence and poor prognosis. Conventional treatments for GC, such as chemotherapy, radiotherapy, and surgical resection, still fail to achieve curative effects because of drug resistance, a mechanism that leads to a reduction of 5-year survival for GC patients. Anoikis, a particular type of programmed cell death, is activated upon cancer cell detachment from the extracellular matrix, playing a crucial role in antagonizing the progression of several malignant tumors. Because GC cells metastasize mainly in the nearby sites in the peritoneum, a better comprehension of the molecular mechanisms involved in the anchorage-independent growth as well as metastatic spreading is crucial to counteract GC progression. In this context, this review critically examines the molecular mechanisms of anoikis, key pathways and regulatory networks, and the role of anoikis resistance in GC. Furthermore, it summarizes potential therapeutic strategies for targeting anoikis-resistant cells. By collecting and analyzing existing literature, this work aims to bridge gaps in the comprehension of the relation between anoikis resistance and GC pathophysiology, providing novel insights and directions for future research in this field.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"528"},"PeriodicalIF":8.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

EZH2 inhibitor SHR2554 enhances the anti-tumor efficacy of HDAC inhibitor Chidamide through STAT1 in T-cell lymphoma. EZH2抑制剂SHR2554通过STAT1增强HDAC抑制剂Chidamide在t细胞淋巴瘤中的抗肿瘤作用。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-14 DOI: 10.1038/s41419-025-07775-x

Jiajin Wu, Dingyao Hu, Hui Yu, Dedao Wang, Yingying Ye, Jiaowu Cao, Tao Pan, Lan Mi, Yuqin Song, Meng Wu, Lingyan Ping, Jun Zhu

引用次数: 0

KDM6A downregulation promotes tumor-prone cytokines expression in cancer-associated fibroblasts by activating enhancers. KDM6A下调通过激活增强子促进癌症相关成纤维细胞中肿瘤易感细胞因子的表达。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-14 DOI: 10.1038/s41419-025-07818-3

Jieying Zhang, Suoyu Xiang, Dan Liu, Xiaomeng Pei, Meng Chen, Yiheng Zhao, Yongbin Wang, Qiong Wang, Lan Kang, Zuoren Yu, Jun Mi, Wujun Xiong

{"title":"KDM6A downregulation promotes tumor-prone cytokines expression in cancer-associated fibroblasts by activating enhancers.","authors":"Jieying Zhang, Suoyu Xiang, Dan Liu, Xiaomeng Pei, Meng Chen, Yiheng Zhao, Yongbin Wang, Qiong Wang, Lan Kang, Zuoren Yu, Jun Mi, Wujun Xiong","doi":"10.1038/s41419-025-07818-3","DOIUrl":"10.1038/s41419-025-07818-3","url":null,"abstract":"Cancer-associated fibroblasts (CAFs) are activated fibroblasts that secrete numerous cytokines and chemokines to accelerate tumor progression. However, the mechanism underlying cytokine production by CAFs remains unclear. This study reports that CAFs isolated from colon cancer tissue, TGF-β1-induced CAFs, or HCT116 co-cultured CAFs secrete more cytokines and growth factors represented by IGF1, ELN, and SFRP2. Mechanistic investigations demonstrate that aerobic glycolysis metabolites fumarate and succinate can induce the transcription of IGF1, ELN, and SFRP2 in CAFs, while α-ketoglutarate (α-KG) can antagonize the induction effect of fumarate and succinate. Moreover, the downregulation of KDM6A in CAFs is observed compared to quiescent fibroblasts (NAFs). Additionally, integrated analysis of ATAC sequencing and RNA sequencing revealed altered chromatin structure during fibroblast activation. CUT-tag sequencing and co-IP assays demonstrate that KDM6A is bound to WDR5, facilitating its association with the COMPASS complex and the polycomb repressive complex at the expected target loci. Depletion of KDM6A disrupts the homeostasis between polycomb and COMPASS complexes, leading to an increase in the expression of IGF1, ELN, and SFRP2. However, the inhibitor GSK-J4, specific for both KDM6A and KDM6B, reduces IGF1 expression, indicating that KDM6B compensates for the demethylase function of KDM6A but cannot replace KDM6A to maintain the homeostasis of COMPASS and polycomb repressive complexes. These findings suggest a metabolism-related epigenetic mechanism for cytokine expression, where reduced KDM6A levels enhance the tumor-promoting effect of CAFs. This may provide insights into why colon cancer is more prevalent in men than in women, since KDM6A is an X-chromosome-associated gene.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"523"},"PeriodicalIF":8.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DHX9-mediated epigenetic silencing of BECN1 contributes to impaired autophagy and tumor progression in breast cancer via recruitment of HDAC5. dhx9介导的BECN1的表观遗传沉默通过HDAC5的募集有助于乳腺癌自噬受损和肿瘤进展。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-14 DOI: 10.1038/s41419-025-07847-y

Ziyang Li, Fang Liu, Fengbei Li, Guopeng Zeng, Xin Wen, Jianan Ding, Jueyu Zhou

{"title":"DHX9-mediated epigenetic silencing of BECN1 contributes to impaired autophagy and tumor progression in breast cancer via recruitment of HDAC5.","authors":"Ziyang Li, Fang Liu, Fengbei Li, Guopeng Zeng, Xin Wen, Jianan Ding, Jueyu Zhou","doi":"10.1038/s41419-025-07847-y","DOIUrl":"10.1038/s41419-025-07847-y","url":null,"abstract":"Autophagy is closely linked to tumorigenesis, progression and metastasis. DHX9 is a member of the DExD/H-box helicase family and plays important roles in transcription, translation, RNA editing and non-coding RNA synthesis. Mounting evidence demonstrates that aberrant expression of DHX9 is associated with the development and progression of several tumors. However, whether DHX9 regulates autophagy deficiency in breast cancer (BC) remains unknown. Herein, we found that DHX9 expression was frequently elevated in BC cells and tissues, which suggested poor survival. The viability and motility of BC cells were irritated by enhanced DHX9 expression. Meanwhile, reduced DHX9 expression postponed tumor development both in vitro and in vivo. Subsequent research revealed that DHX9 knockdown suppressed the activation of the mTOR signaling pathway and accelerated autophagic flux by promoting the formation of autophagosomes in BC cells. Mechanistically, DHX9 occupied the proximal promoter of BECN1 and repressed its transcription. DHX9-mediated BECN1 inhibition required histone deacetylase (HDAC) activity. HDAC5 was recruited to the nucleus and co-localized with DHX9 at the BECN1 promoter, mediating the deacetylation of histone H3 and ultimately inhibited BECN1 transcription. Importantly, the tumor-suppressive effect of DHX9 knockdown was reversed by BECN1 downregulation. In conclusion, the previously unrecognized significance of DHX9 in mediating the epigenetic silencing of BECN1, which is essential for autophagy and tumorigenesis, highlights its potential as an effective biomarker as well as a prospective therapeutic candidate for BC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"524"},"PeriodicalIF":8.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12260095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SUMOylation of the lysine-less tumor suppressor p14ARF counters ubiquitylation-dependent degradation. 无赖氨酸肿瘤抑制因子p14ARF的summoylation对抗泛素化依赖性降解。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-12 DOI: 10.1038/s41419-025-07854-z

Ahmed El Motiam, Yanis H Bouzaher, Haifen Chen, Rocío Seoane, Santiago Vidal, María Blanquer, Rocío M Tolosa, Beatriz Rodríguez-Lemus, José A Herrera-Gavilán, Anxo Vidal, Ignacio Palmero, Manuel S Rodríguez, James D Sutherland, Rosa Barrio, Dimitris Xirodimas, Manuel Collado, Rod Bremner, Carmen Rivas

{"title":"SUMOylation of the lysine-less tumor suppressor p14ARF counters ubiquitylation-dependent degradation.","authors":"Ahmed El Motiam, Yanis H Bouzaher, Haifen Chen, Rocío Seoane, Santiago Vidal, María Blanquer, Rocío M Tolosa, Beatriz Rodríguez-Lemus, José A Herrera-Gavilán, Anxo Vidal, Ignacio Palmero, Manuel S Rodríguez, James D Sutherland, Rosa Barrio, Dimitris Xirodimas, Manuel Collado, Rod Bremner, Carmen Rivas","doi":"10.1038/s41419-025-07854-z","DOIUrl":"10.1038/s41419-025-07854-z","url":null,"abstract":"p14ARF is a lysine-less tumor suppressor that enhances SUMOylation of its interactors. Although p14ARF is known to interact with the E2 SUMO conjugating enzyme UBC9, the link between ARF and SUMOylation is poorly understood and the potential impact of SUMOylation on p14ARF is unknown. Here we show that SUMO2 conjugates to the N-terminus of p14ARF and stabilizes it. Either depleting UBC9 or pharmacologically inhibiting SUMOylation, induces p14ARF degradation. In contrast, blocking ubiquitination or NEDDylation, with TAK-243 or MLN4924/Pevonedistat respectively, increases p14ARF SUMOylation and restores p14ARF levels when SUMOylation is blocked. Treatment with MLN4924 also causes p14ARF-dependent mRNA upregulation of the SUMOylation components SUMO1, SUMO2, and UBC9, globally augmenting SUMOylation. Finally, p14ARF contributes to MLN4924-driven cytotoxicity of prostate cancer cells. Our results provide evidence that, despite lacking lysine, p14ARF is SUMOylated and this modification is critical to counter ubiquitin driven degradation and establishes a new link between inhibition of NEDDylation and SUMOylation.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"519"},"PeriodicalIF":8.1,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

O-GlcNAcylation of METTL3 drives hepatocellular carcinoma progression by upregulating MCM10 expression in an m6A-IGF2BP3-dependent manner. METTL3的o - glcn酰化通过m6a - igf2bp3依赖的方式上调MCM10的表达来驱动肝细胞癌的进展。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-12 DOI: 10.1038/s41419-025-07844-1

Zhen Chen, Jiaxin Yin, Zhongqi Feng, Yanlai Zhang, Li Liang, Xiaojun Wang, Kai Wang, Ni Tang

{"title":"O-GlcNAcylation of METTL3 drives hepatocellular carcinoma progression by upregulating MCM10 expression in an m6A-IGF2BP3-dependent manner.","authors":"Zhen Chen, Jiaxin Yin, Zhongqi Feng, Yanlai Zhang, Li Liang, Xiaojun Wang, Kai Wang, Ni Tang","doi":"10.1038/s41419-025-07844-1","DOIUrl":"10.1038/s41419-025-07844-1","url":null,"abstract":"The m6A methyltransferase METTL3 is a key regulator of RNA m6A modification, which plays a critical role in cancer development. Despite the significance of METTL3 in hepatocellular carcinoma (HCC), its post-translational modifications and their functional implications in HCC remain poorly understood. The present study reveals that METTL3 undergoes O-GlcNAcylation, which enhances its stability and promotes HCC progression. Specific O-GlcNAcylation sites (T186/S192/S193) in METTL3 are identified. O-GlcNAc modification reduces METTL3 ubiquitination, thereby increasing protein stability, and enhances its interaction with WTAP, thereby sustaining m6A levels in hepatoma cells. Notably, METTL3 O-GlcNAcylation upregulates the expression of minichromosome maintenance protein 10 (MCM10) by stabilizing its mRNA via an m6A-IGF2BP3-dependent manner. Targeting METTL3 O-GlcNAcylation with designed peptides effectively inhibits HCC growth both in vitro and in vivo. Collectively, our findings provide insights into the regulatory role of O-GlcNAcylation in modulating the m6A epitranscriptome and suggest the potential therapeutic relevance of targeting METTL3 O-GlcNAcylation in HCC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"518"},"PeriodicalIF":8.1,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CENPT prevents renal cell carcinoma against ferroptosis by enhancing the synthesis of glutathione. CENPT通过增强谷胱甘肽的合成来预防肾细胞癌对铁下垂。

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2025-07-12 DOI: 10.1038/s41419-025-07848-x

Han Yang, Zongliang Zhang, Ninghan Feng, Kai Zhao, Yulian Zhang, Xinbao Yin, Guanqun Zhu, Zhenlin Wang, Xuechuan Yan, Xueyu Li, Zhaofeng Li, Qinglei Wang, Yixin Qi, Peng Zhao, Tianzhen He, Ke Wang

{"title":"CENPT prevents renal cell carcinoma against ferroptosis by enhancing the synthesis of glutathione.","authors":"Han Yang, Zongliang Zhang, Ninghan Feng, Kai Zhao, Yulian Zhang, Xinbao Yin, Guanqun Zhu, Zhenlin Wang, Xuechuan Yan, Xueyu Li, Zhaofeng Li, Qinglei Wang, Yixin Qi, Peng Zhao, Tianzhen He, Ke Wang","doi":"10.1038/s41419-025-07848-x","DOIUrl":"10.1038/s41419-025-07848-x","url":null,"abstract":"Cancer is characterized by chromosomal instability (CIN), which leads to tumor heterogeneity and other malignant features. CIN is caused by abnormal centromere and kinetochore function, which results in aneuploidy, rearrangements, and micronucleus production. Centromere and kinetochore gene misexpression plays a vital role in tumor progression. Here we show that Centromere Protein T (CENPT) is highly expressed in renal carcinoma (RCC) and promotes the tumor proliferation and metastasis of RCC. CENPT is found to be critical for regulating the glutathione (GSH) metabolism pathway because it interacts with γ-glutamyl-cysteine ligase catalytic subunit (GCLC), consequently reducing reactive oxygen species levels and inhibiting ferroptosis. Mechanistically, CENPT increases the catalytic activity of GCLC by directly binding to GCLC ∆213-424aa competitively with glutamate-cysteine ligase modifier subunit (GCLM), consequently induces the GSH synthesis. In turn, GSH increases CENPT expression via transcriptional regulation mediated by the transcription factor ATF2, forming a CENPT-GCLC-GSH feedback loop that enhances the pro-carcinogenic effect of this axis in RCC. Our study identifies CENPT a potential target for RCC via forming a CENPT-GCLC-GSH feedback loop to inhibit ferroptosis. This may support a promising treatment strategy for RCC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"517"},"PeriodicalIF":8.1,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0