Shuai You, Ma Zhonghua, Ju Jie, Li Chunxiao, Bai Xiaorong, Yue Jian, Wang Xue, Yuan Peng, Qian Haili
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Endoscopy, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
Apoptosis. 2025 Feb;30(1-2):226-238. doi: 10.1007/s10495-024-02037-1. Epub 2024 Dec 3.
Cell pyroptosis is a form of programmed cell death, with Gasdermin-D (GSDMD) acting as its key executor. While activating pyroptosis represents a promising therapeutic strategy for cancer, the regulatory mechanisms governing GSDMD expression during cell death remain poorly understood. In this study, we identified METTL3 as a negative regulator of GSDMD-mediated pyroptosis, with high expression in breast cancer (BC) cells. YTHDF2 was found to recognize the m6A modification of GSDMD, thereby decreasing its stability. Finally, in vivo experiments further demonstrated the inhibitory effect of the METTL3 inhibitor STM2457 on tumors. Overall, these findings suggest that inhibition of METTL3 can enhance GSDMD-mediated pyroptosis and reveal a novel regulatory mechanism governing GSDMD expression, presenting a novel strategy for cancer treatment.
细胞焦亡是一种程序性细胞死亡形式，Gasdermin-D（GSDMD）作为其关键执行者。虽然激活焦亡是一种有前景的癌症治疗策略，但细胞死亡过程中调控GSDMD表达的机制仍知之甚少。在本研究中，我们确定METTL3是GSDMD介导的焦亡的负调节因子，在乳腺癌（BC）细胞中高表达。发现YTHDF2可识别GSDMD的m6A修饰，从而降低其稳定性。最后，体内实验进一步证明了METTL3抑制剂STM2457对肿瘤的抑制作用。总体而言，这些发现表明抑制METTL3可增强GSDMD介导的焦亡，并揭示了一种调控GSDMD表达的新机制，为癌症治疗提供了一种新策略。
