Glycolytic reprogramming in endometriosis: molecular mechanisms, immune modulation, and non-hormonal therapeutic opportunities

Endometriosis is a chronic gynecological disorder characterized by ectopic tissue growth and significant morbidity, yet current hormonal and surgical treatments often fail to prevent recurrence or entail severe side effects. Increasing evidence highlights metabolic reprogramming, specifically aerobic glycolysis (the Warburg effect), as a fundamental driver of endometriotic lesion pathogenesis. This narrative review synthesizes current research on the regulatory mechanisms and therapeutic potential of targeting glycolytic dysregulation in endometriosis. We examine the aberrant upregulation of rate-limiting enzymes, including hexokinase 2 (HK2), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), and pyruvate kinase M2 (PKM2), driven by signaling axes such as ALKBH5-HK2, PAK5-PKM2, and S1PR4/mTOR. The review further elucidates how enhanced glycolytic flux and lactate accumulation promote cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) while orchestrating an immunosuppressive microenvironment via M2 macrophage polarization and histone lactylation. Furthermore, we evaluate emerging non-hormonal therapeutic strategies, including specific glycolysis inhibitors and natural compounds, and discuss the utility of immune-metabolic gene signatures for non-invasive diagnosis. Highlighting these metabolic vulnerabilities offers promising avenues for precision medicine to improve clinical management and patient outcomes in endometriosis.