METTL3-mediated m6A modification promotes ferroptosis in adenomyosis through GPX4 in a YTHDF1-dependent manner

Adenomyosis, a prevalent gynecologic disorder affecting women of reproductive age, is characterized by the presence of ectopic endometrial tissue within the myometrium. The involvement and underlying mechanisms of ferroptosis in adenomyosis have not been fully elucidated. Recently, m6A RNA modification has been found to regulate various biological processes. This study aimed to investigate the status of ferroptosis in adenomyosis and explore how m6A modification regulates key genes associated with ferroptosis. The research revealed ferroptosis present in both eutopic and ectopic endometrial tissues of individuals with adenomyosis. In addition, a decrease in RNA m6A modification levels and a reduction in GPX4 protein expression were observed. GPX4 may serve as a biomarker reflecting the severity of adenomyosis, as it showed a significant negative correlation with CA125 levels, uterine size, and the severity of dysmenorrhea in patients. Mechanistically, the study demonstrated that the downregulation of METTL3 in endometrial stromal cells results in reduced m6A modification on GPX4 mRNA. Consequently, GPX4 mRNA translation is downregulated by YTHDF1, leading to ferroptosis in eutopic and ectopic endometrial cells. These findings contribute to a deeper understanding of the mechanisms underlying adenomyosis and provide valuable insights into potential therapeutic strategies targeting ferroptosis in the management of adenomyosis.