YTHDF3 promotes angiogenesis in endometriosis by enhancing the translation efficiency of PFKFB3.

Angiogenesis plays a critical role in the progression of endometriosis, with enhanced glycolysis accelerating pathological angiogenesis. Prior research has identified a central role for N6-methyladenosine (m6A) modification in regulating glycolytic processes. This study investigates the involvement of m6A-mediated mechanisms in the regulation of glycolysis and angiogenesis in endometriosis. Here, we report that PFKFB3 is significantly upregulated in vascular endothelial cells of ectopic endometrial tissues from humans and mice, correlating with elevated expression of YTHDF3. Specific deletion of Ythdf3 in endothelial cells reduces PFKFB3 protein levels and suppresses angiogenesis in ectopic endometrial lesions. Mechanistically, PFKFB3 mRNA displays increased m6A modifications in endometrial microvascular endothelial cells (EMECs). METTL3 enhances m6A modification of PFKFB3 mRNA, which is recognized by YTHDF3, promoting PFKFB3 translation and glycolytic activity, thus facilitating tube formation, migration, and proliferation of ovarian microvascular endothelial cells (OMECs). Moreover, estrogen upregulates both METTL3 and PFKFB3 via the estrogen receptor ERα. Collectively, these findings establish the YTHDF3-m6A-PFKFB3 pathway as a critical driver of angiogenesis in endometriosis, suggesting that targeting this pathway represents a promising therapeutic strategy.