Abstract

YTHDF2 expression is reduced in ectopic endometria and eESCs. • YTHDF2 suppresses EMs progression in vitro and in vivo. • Hypoxia/HIF-1α downregulates YTHDF2 via HDAC11-mediated promoter deacetylation. • YTHDF2 destabilizes NFE2L1 mRNA in an m 6 A-dependent manner. • NFE2L1 activates STAT3/CARD11 to drive NF-κB signaling in YTHDF2-deficient cells. Endometriosis (EMs) is a chronic inflammatory disease characterized by ectopic growth of endometrial-like tissues. N 6 -methyladenosine (m 6 A) modification regulates diverse cellular processes, yet its role in EMs remains unclear. Here, we show that the m 6 A reader YTHDF2 is downregulated in ectopic tissue and endometrial stromal cells. Overexpression of YTHDF2 in HESCs suppresses proliferation and migration while promoting apoptosis, whereas its knockdown exerts opposite effects. In vivo, AAV9-mediated Ythdf2 delivery inhibits lesion growth, while inhibition of YTHDF2 accelerates disease progression. Mechanistically, hypoxia induces HDAC11 via HIF-1α, reducing acetylation of the YTHDF2 promoter and leading to transcriptional silencing. RNA-seq reveals that YTHDF2 loss activates NF-κB signaling. Integrative MeRIP-seq, RIP-seq, and scRNA-seq analyses identify NFE2L1 as a direct downstream target whose mRNA stability is enhanced upon YTHDF2 depletion in an m 6 A-dependent manner. Elevated NFE2L1 activates STAT3 and CARD11, potent NF-κB inducers. Collectively, our study uncovers a mechanism whereby epigenetic silencing of YTHDF2 drives EMs progression through the NFE2L1-NF-κB axis, suggesting YTHDF2 as a potential therapeutic target. Download: Download high-res image (120KB) Download: Download full-size image