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

Xiaosa Li, Li X, Jiale Wang, Wang J, Yuan L, Liang Yuan, Wang Y, Yuqi Wang, Jinzhi Wei, Wei J, Ping Li, Li P, Wang R, Runxin Wang, Xingyan Xu, Xu X, Qiuwen Mai, Mai Q, Liu J, Junxiu Liu, Lin H, Huiping Lin, Xiaodong Fu, Fu X
Angiogenesis · 2026 · vol. 29(4) · doi:10.1007/s10456-026-10095-z · PMID:42776305 · W7214096832
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In endometriosis, estrogen upregulates METTL3 to increase m6A modification of PFKFB3 mRNA, which YTHDF3 recognizes to enhance translation and promote angiogenesis through glycolytic activity in endothelial cells.

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Abstract

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.

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MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Neovascularization, Pathologic Neovascularization, Pathologic Neovascularization, Pathologic Neovascularization, Pathologic Neovascularization, Pathologic Neovascularization, Pathologic

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Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

References (43)

SciLite annotations

chemicals 2
methyladenosine estrogen
organisms 2
humans mus sp.

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