Metabolic activation of LDHA by ERRα represses inflammasome-dependent pyroptosis and promotes ovarian cancer chemoresistance

Chemoresistance remains a major unmet challenge in the clinical management of ovarian cancer. As a metabolism-associated malignancy, the poor prognosis and frequent chemoresistance of ovarian cancer are closely linked to metabolic reprogramming. In this study, we identify estrogen-related receptor α (ERRα) as a key regulator of metabolic plasticity and chemoresistance in ovarian cancer. Bioinformatic analyses of pan-cancer datasets and chemoresistant ovarian cancer samples reveal that high expression of ERRα and the glycolytic rate-limiting enzyme lactate dehydrogenase A (LDHA) is associated with poor clinical outcomes. Elevated serum LDH levels in chemoresistant patients further underscore the importance of metabolic reprogramming in the development of chemoresistance. Mechanistically, ChIP-seq, dual-luciferase reporter assays, and enzymatic colorimetric assays demonstrate that ERRα directly binds to the LDHA promoter region (5'-AGAAGGTCG-3'), activating its transcription and enhancing glycolysis and the production of its end-product, lactate. Scanning electron microscopy, immunofluorescence, Western Blot, and other molecular functional assays show that the ERRα/LDHA axis drives lactate accumulation, downregulates inflammasome-related proteins (NLRP3, caspase-1, GSDMD and GSDMD-N), thereby suppressing pyroptosis and promoting resistance to cisplatin, carboplatin, and paclitaxel in ovarian cancer cells. Pharmacological inhibition of ERRα with XCT790 restores sensitivity to chemotherapeutic agents. In a mouse xenograft model, targeting ERRα enhances the therapeutic efficacy of chemotherapy. Collectively, these findings reveal that the ERRα-LDHA axis increases lactate production, bridging glycolytic metabolism and the suppression of pyroptosis, thereby facilitating chemoresistance in ovarian cancer. Targeting the ERRα/LDHA pathway and developing ERRα inhibitors may represent promising strategies to overcome chemoresistance in ovarian cancer.ERRα targets the promoter region of LDHA, promoting its transcription and the production of the glycolytic product lactate, inhibiting the NLRP3/caspase-1/GSDMD pathway, reducing cell pyroptosis, and helping ovarian cancer cells resist the cytotoxic effects of carboplatin and paclitaxel. Created in BioRender. Ren, Y. (2025) https://BioRender.com/qeh0dw8.