Hypoxia-mediated epigenetic silencing of YTHDF2 promotes endometriosis progression via the NFE2L1-NF-κB axis

Tao Wang, Wang T, Xiaotong Peng, Peng X, Pusheng Yang, Yang P, Me Ji, Ji M, Yaxin Miao, Miao Y, Jiaxin Zhang, Zhang J, Wenwen Liu, Liu W, Zhu Y, Yiping Zhu, Ming Tang, Tang M, Sun J, Jing Sun
International journal of biological macromolecules · 2026 · vol. 367 , pp. 152621 · doi:10.1016/j.ijbiomac.2026.152621 · PMID:42162597 · W7161723411
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Hypoxia epigenetically silences YTHDF2, promoting endometriosis progression through the NFE2L1-NF-κB signaling pathway.

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Abstract

Endometriosis (EMs) is a chronic inflammatory disease characterized by ectopic growth of endometrial-like tissues. N6-methyladenosine (m6A) modification regulates diverse cellular processes, yet its role in EMs remains unclear. Here, we show that the m6A 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 m6A-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.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis

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References (58)

SciLite annotations

chemicals 1
methyladenosine

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