Elevated Histone Lactylation Mediates Ferroptosis Resistance in Endometriosis Through the METTL3‐Regulated HIF1A/HMOX1 Signaling Pathway

Endometriosis (EMs) is a chronic gynecologic condition characterized by the growth of endometrial stromal and glandular tissue outside the uterine cavity of unknown etiology. Currently, ferroptosis resistance, increased glycolysis, and increased lactate production are identified in EMs. Histone lactylation is a lactate-derived posttranslational modification that is recognized primarily for its role in epigenetic regulation. In this study, it is demonstrated that increased histone lactylation contributes to ferroptosis resistance in ectopic endometrial stromal cells (EESCs). Mechanistically, histone lactylation mediates ferroptosis resistance through the hypoxia-inducible factor 1 alpha (HIF1A)/heme oxygenase 1 (HMOX1) signaling pathway, which is regulated by methyltransferase like 3 (METTL3). In vivo experiments reveal that combination therapy with 2-deoxy-D-glucose (2-DG) and erastin is more effective for the treatment of EMs. Together, the findings provide a theoretical basis for the pathogenesis of EMs and suggest that a combined treatment that inhibits histone lactylation and induces ferroptosis is an effective treatment for EMs.