The researchers began from a metabolic observation that has been gaining traction across vascular biology. When blood vessels grow abnormally, the endothelial cells that line them shift their energy production toward glycolysis, the rapid, oxygen-independent breakdown of glucose. The enzyme PFKFB3, an allosteric activator of the glycolytic pathway, is central to this switch. Earlier studies showed that blocking PFKFB3 even partially reduces pathological vessel sprouting, and that endothelial cells lacking it cannot form vessels efficiently. What remained unclear was how PFKFB3 protein levels are controlled in the endothelial cells infiltrating endometriotic lesions.

To answer that question, the team examined vascular endothelial cells in ectopic endometrial tissue taken from both human patients and mouse models. In both species, they found that PFKFB3 was significantly upregulated, and that this elevation tracked closely with increased expression of YTHDF3, a member of the YTH domain family of proteins. These proteins are known as readers of N6-methyladenosine, or m6A, the most abundant internal chemical modification in eukaryotic messenger RNA. The m6A mark does not change the genetic code; instead, it influences the fate of each transcript, dictating whether it is translated into protein, degraded, or stored.

The causal importance of YTHDF3 became clear in genetic experiments. When the researchers specifically deleted the Ythdf3 gene in endothelial cells of mice, PFKFB3 protein levels dropped and angiogenesis within the ectopic endometrial lesions was suppressed. Notably, the manipulation targeted the translation step rather than the abundance of the mRNA itself. This distinction matters because it points to a regulatory layer that most existing therapies never touch: the efficiency with which a stable message is actually converted into functional protein.

Delving into the mechanism, the team focused on endometrial microvascular endothelial cells, where the PFKFB3 messenger RNA carried increased m6A modifications. The writer of those marks is METTL3, the catalytic core of the enzyme complex that installs m6A on transcripts. According to the study, METTL3 enhances m6A modification of the PFKFB3 mRNA, and YTHDF3 then recognizes these modified sites, promoting the translation of PFKFB3 and thereby raising glycolytic activity within the cells. The metabolic boost translates directly into cellular behavior: ovarian microvascular endothelial cells showed enhanced tube formation, migration and proliferation when the pathway was active.

The m6A system has been implicated in metabolism and angiogenesis before. Previous work showed that the modification regulates glycolysis in cancer cells through enzymes such as PDK4, and reviews have catalogued multiple RNA modifications shaping vessel growth. YTHDF3 itself has a colorful track record: it has been shown to promote the translation of m6A-enriched transcripts in breast cancer brain metastasis, to modulate antiviral interferon responses through FOXO3, and to assist translation by recruiting initiation factors. The new study extends this translation-enhancing role into a gynecological disease context, linking it to a hormone-driven pathology.

That hormonal link is perhaps the most clinically provocative element of the findings. Endometriosis is an estrogen-dependent disease, and the researchers found that estrogen upregulates both METTL3 and PFKFB3 through the estrogen receptor ERα. In other words, the very hormone that drives the growth of endometrial tissue also appears to arm the vessel-feeding machinery that sustains it, by amplifying the RNA-modification writer and the metabolic target it acts upon. This creates a coherent loop in which hormonal signaling, epitranscriptomic regulation and endothelial metabolism converge to support lesion establishment and expansion.

Angiogenesis has long been recognized as a requirement for endometriotic lesions to survive and grow after they are seeded within the pelvic cavity, and anti-angiogenic strategies have been proposed as adjunct therapies for years. The difficulty has been specificity: vessels in healing wounds and normal tissues also depend on glycolytic endothelial cells, so systemic blockade of PFKFB3 carries risks. The YTHDF3-m6A-PFKFB3 axis offers a more layered target. Interfering with the reader protein or with the estrogen-driven upregulation of METTL3 could, in principle, blunt pathological vessel growth in lesions while sparing some of the baseline vascular functions that depend on other regulators.

The study’s authors, led by Xiaosa Li, Jiale Wang and Liang Yuan as co-first authors under the direction of senior investigators including Xiaodong Fu, Huiping Lin and Junxiu Liu, argue that their findings establish the YTHDF3-m6A-PFKFB3 pathway as a critical driver of angiogenesis in endometriosis and suggest that targeting this pathway represents a promising therapeutic strategy. The work was supported by the National Natural Science Foundation of China and by a research fund from Guangzhou, and the authors declare no competing interests.

As with any mechanistic study, the road from molecular circuit to clinic is long. Animal models and cell culture systems capture only part of the human disease, and m6A readers act on many transcripts at once, so systemic interventions would need careful dosing and delivery strategies. Still, the study adds endometriosis to a growing list of conditions in which chemical tags on RNA, rather than changes in the genes themselves, determine whether disease-associated cells thrive. For millions of patients whose pain and fertility struggles have outpaced available treatments, the idea that a single reader protein controls the fuel supply of the vessels feeding their lesions is a compelling new lead, and one that researchers are likely to pursue with urgency.

Subject of Research: m6A reader YTHDF3 promotes angiogenesis in endometriosis by enhancing PFKFB3 translation

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

Article References: Li, X., Wang, J., Yuan, L., Wang, Y., Wei, J., Li, P., Wang, R., Xu, X., Mai, Q., Liu, J., Lin, H., & Fu, X. (2026). YTHDF3 promotes angiogenesis in endometriosis by enhancing the translation efficiency of PFKFB3. Angiogenesis, 29(4), Article 70. https://doi.org/10.1007/s10456-026-10095-z

Image Credits: AI Generated

DOI: 10.1007/s10456-026-10095-z

Keywords: endometriosis, angiogenesis, YTHDF3, m6A, PFKFB3, METTL3, glycolysis, endothelial cells, estrogen, translation, PFKFB3 mRNA, vascular biology