A novel mechanism of FTO modulating the progression of endometriosis through mediating the m6A methylation of GEF-H1 in a YTHDF1-dependent manner

作者：Xinyu Ding, Huaying Zhang, Jiahao Chen, Mengjie Yang, Zhixiong Huang, Yi‐Hong Lei, Qin-Kun Sun, Jian-Bin Bai, Dianchao Lin, Jianfa Lan, Lulu Ren, Zheng‐Yi Chen, Weidong Zhou, Qionghua Chen · 发表于：Molecular Medicine · 年份：2025 · DOI：10.1186/s10020-025-01130-8 · 被引用次数：7 · 研究领域：RNA modifications and cancer、Endometriosis Research and Treatment、Gestational Trophoblastic Disease Studies

BACKGROUND: Endometriosis (EMs) is a condition characterized by the growth of endometrial tissue outside the uterine cavity. Although this condition is benign, it has cancer-like features. N6-methyladenosine (m6A) is a common RNA modification involved in diverse biological processes, but its role in EMs remains unclear. METHODS: A human endometrial stromal cell line (HESCs), primary eutopic endometrial stromal cells (Eu-ESCs), primary ectopic endometrial stromal cells (Ec-ESCs), and clinical samples were used in this study. A colorimetric assay was used to measure methylation levels in clinical and mouse EMs samples. Functional assays (CCK-8, EdU, Transwell, and wound healing) were used to evaluate phenotypic changes. m6A immunoprecipitation sequencing (MeRIP-seq) identified downstream targets. Mechanistic studies were conducted via qRT‒PCR, Western blot, RNA immunoprecipitation (RIP), dual-luciferase reporter, and RNA stability assays. RESULTS: We detected aberrantly low levels of m6A within endometriotic lesions, which was attributed to increased expression of the m6A eraser fat mass and obesity-associated protein (FTO). Notably, estrogen and inflammatory factors, which are recognized as pathogenic agents in EMs amplify FTO expression while suppressing m6A levels. In vitro experiments demonstrated that overexpression of FTO in endometrial stromal cells leads to a reduction in m6A levels and concomitantly promotes their proliferation, migration, and invasion. Furthermore, bo...