Decreased Glycolysis due to LDHA m6A methylation in Endometrium of endometriosis impairs its decidualization and contributes to related infertility.

Abstract

Endometriosis-related infertility is a prevalent reproductive health concern of global significance. Functional abnormalities of the endometrium are increasingly recognized as a pivotal contributor to infertility in affected individuals. In the present study, a significant reduction in glycolytic activity was observed in secretory-phase endometrial tissues obtained from patients with endometriosis, and this metabolic defect was attributed to downregulated expression of lactate dehydrogenase A (LDHA). This impaired glycolysis was found to induce defective endometrial decidualization and contribute to endometriosis-related infertility in a mouse model. Mechanistically, inhibition of LDHA promoted the production of reactive oxygen species (ROS) and apoptosis of endometrial stromal cells, ultimately resulting in compromised stromal cell decidualization. Furthermore, reduced LDHA expression was confirmed in the eutopic endometrium of patients with endometriosis, which was associated with decreased N6-methyladenosine (m⁶A) demethylation activity. This attenuation of m⁶A demethylation was, in turn, attributed to the downregulated expression of alkB homolog 5 (ALKBH5)-a key enzyme responsible for m⁶A demethylation modification. Collectively, our findings demonstrate that elevated m⁶A methylation levels in the eutopic endometrium of patients with endometriosis impair endometrial glycolytic metabolism and decidualization of endometrial stromal cells, thereby contributing to endometriosis-related infertility. This pathological cascade is mediated by the downregulation of LDHA expression.