NAT10 drives endometriosis progression through acetylation and stabilization of TGFB1 mRNA.

Endometriosis, a gynecological disorder marked by pelvic pain and infertility, has its pathogenesis and pathophysiology significantly influenced by epigenetics, as these factors have been well characterized. However, the role of RNA-mediated epigenetic regulation in endometriosis remains to be elucidated. In our study, we found that N4-acetylcytidine (acC) RNA modification and N-acetyltransferase 10 (NAT10) were significantly upregulated in endometrial lesions compared to eutopic endometrium. Knockdown of NAT10 suppressed endometrial epithelial cell proliferation, epithelial-to-mesenchymal transition (EMT), and cell cycle processes in vitro. RNA-seq and acRIP-seq analyses revealed that the knockdown of NAT10 impaired cell proliferation and the TGF-beta signaling pathway. We further identified that acC RNA modification enhanced TGFB1 mRNA stability and expression levels, and inhibition of NAT10 activity by Remodelin effectively suppressed the growth of ectopic lesions in an endometriosis mouse model. Collectively, our findings reveal that increased NAT10-mediated acC modification enhances TGFB1 mRNA stability, thereby promoting the development of endometriosis. This discovery lays the molecular foundation for future therapeutic approaches targeting endometriosis.