The N6-methyladenosine writer METTL3 promotes breast cancer progression through YTHDF2-dependent posttranscriptional silencing of GSDMD.

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.
Competing Interests: Declarations. Competing interest: The authors declare no competing interests. Ethical approval: This study was approved by the Institutional Research Ethics Committee of the Cancer Hospital at the Chinese Academy of Medical Sciences, in accordance with the Declaration of Helsinki. All animal experiments were approved by the Animal Experiment Ethics Committee of the Chinese Academy of Medical Sciences Cancer Hospital.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)