RNF34 restrains endometriosis progression by promoting PKM2 ubiquitination and suppressing glycolysis.

Metabolic reprogramming, particularly enhanced glycolysis, is an important feature of endometriosis, yet the upstream posttranslational mechanisms governing this metabolic phenotype remain poorly understood. Transcriptomic analysis and clinical tissue validation revealed reduced RNF34 expression in endometriotic tissues and an inverse association between RNF34 and pyruvate kinase M2 (PKM2). Mass spectrometry analysis revealed that PKM2 is an RNF34-interacting protein, and biochemical assays further demonstrated this direct association. Mechanistically, RNF34 promoted PKM2 ubiquitination and reduced its protein stability in an E3 ligase-dependent manner. RNF34 suppressed glycolytic activity, proliferation, migration, and invasion in endometriotic and endometrial stromal cells, whereas reciprocal PKM2 rescue experiments supported the role of PKM2 as an important functional mediator of these effects. In a donor-recipient mouse model, RNF34-deficient uterine tissue generated larger endometriotic lesions, whereas PKM2 inhibition attenuated the increased lesion burden, supporting the role of PKM2 as a functional downstream mediator of RNF34 in vivo. As a pharmacological extension, curcumin increased RNF34 protein abundance and suppressed endometriosis-associated cellular phenotypes, whereas RNF34 depletion attenuated these effects. Curcumin also reduced endometriotic lesion burden in vivo. Collectively, these findings define an RNF34-PKM2 regulatory axis that links ubiquitin-dependent control of PKM2 stability to glycolytic reprogramming and endometriosis progression and support the pharmacological relevance of RNF34 in endometriosis.