ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer

Abstract Background Tumor cells can resist chemotherapy-induced pyroptosis through glycolytic reprogramming. Estrogen-related receptor alpha (ERRα) is a central regulator of cellular energy metabolism associated with poor cancer prognosis. Herein, we refine the oncogenic role of ERRα in the pyroptosis pathway and glycolytic metabolism. Methods The protein interaction between ERRα and HIF-1α was verified by Co-immunoprecipitation. The transcriptional binding sites of ERRα and NLRP3 were confirmed by dual-luciferase reporter assay. Flow cytometry, transmission electron microscopy, and extracellular acidification rate analysis were performed to investigate the effect of ERRα on the pyroptosis pathway and glycolytic metabolism. This experiments were further confirmed in EC-derived organoids and nude mice. In addition, the expression of ERRα-related pyroptosis genes was analyzed by the The Cancer Genome Atlas database. Results Triggered by a hypoxic microenvironment, highly-expressed-ERRα could bind to the promoter of NLRP3 and inhibit caspase-1/GSDMD signaling, which reduced inflammasome activation and increased pyroptosis resistance, thereby resulting in cancer cells resistant to cisplatin. Moreover, ERRα activated pyruvate kinase M2 (PKM2), a glycolytic rate-limiting enzyme, to bridge glycolytic metabolism and pyroptosis in endometrial cancer (EC). This phenomenon was further confirmed in EC-derived organoids and nude mice. The Cancer Genome Atlas database analysis showed that ERRα participated in glycolysis and programmed cell death, which resulted in the progression of EC. Conclusions ERRα inhibits pyroptosis in an NLRP3-dependent manner and induces glycolytic metabolism, resulting in cisplatin resistance in EC cells.