Gentianine suppresses renal cell carcinoma progression via direct interaction with KDM5B and ferroptosis activation.

Gentianine (GTN), a bioactive alkaloid isolated from Gentiana scabra Bunge, exhibits broad therapeutic potential in inflammatory and metabolic diseases, yet its antitumor properties and molecular mechanisms in renal cell carcinoma (RCC) remain unexplored. In this study, we demonstrate that GTN significantly inhibits RCC cell proliferation and metastasis in vitro and suppresses tumor growth in xenograft models. Mechanistic investigations revealed that GTN directly interacts with the histone demethylase KDM5B, preventing its degradation. The increased KDM5B expression decreased H3K4me3 level at the promoters of ferroptosis-related genes GPX4 and SLC7A11, leading to transcriptional repression of these antioxidant regulators. Consequently, GTN induces ferroptosis hallmarks, including glutathione (GSH) depletion, iron-dependent lipid peroxidation, and mitochondrial dysfunction. Importantly, combining GTN with the ferroptosis inducer RSL3 synergistically enhances antitumor efficacy in vivo. Our study unveils a previously unrecognized KDM5B/ferroptosis axis through which GTN exerts its antitumor effects, positioning GTN as a promising lead compound for ferroptosis-targeted therapy in RCC.