Gingerenone A inhibits LDHA-mediated glycolysis and restores sunitinib sensitivity in renal cell carcinoma.

Renal cell carcinoma (RCC) remains a major clinical challenge due to its high metastatic potential, poor prognosis, and frequent development of resistance to tyrosine kinase inhibitors (TKIs) such as sunitinib. Metabolic reprogramming, particularly enhanced aerobic glycolysis, plays a crucial role in RCC progression and drug resistance. In this study, we identified gingerenone A (GA), a natural phenolic compound derived from Zingiber officinale, as a potent metabolic inhibitor with therapeutic potential in RCC. Through a combination of network pharmacology, molecular docking, and experimental validation, GA was shown to target lactate dehydrogenase A (LDHA), suppressing glycolysis and reducing lactate production, ATP generation, and glucose uptake. This metabolic inhibition further disrupted the stabilization of Hypoxia-inducible factor 1-alpha (HIF-1α) and downregulated its downstream angiogenic effectors VEGFA and VEGFR2. Notably, exogenous lactate supplementation reversed these effects, confirming the metabolic basis of GA' s action. Importantly, GA significantly enhanced the anti-tumor efficacy of sunitinib in both sensitive and resistant RCC models. GA not only reduced the IC50 of sunitinib and showed synergistic cytotoxicity in vitro, but also restored sunitinib responsiveness in resistant cells and further suppressed tumor growth in vivo, without affecting body weight. This study reveals that GA inhibits LDHA-driven glycolysis and disrupts the HIF-1α/VEGFA/VEGFR2 signaling pathway in RCC. By enhancing the therapeutic efficacy of sunitinib and overcoming drug resistance, GA offers a promising metabolic-targeted adjuvant strategy for RCC treatment.