Cyclomulberrin represses renal cell carcinoma progression via ferroptosis activation

Renal cell carcinoma (RCC) is one of the most common malignancies in the genitourinary system. Cyclomulberrin (CyM), a natural prenylated flavonoid, has shown anti-tumor potential. However, the efficacy and potential mechanisms of this treatment in RCC remain unclear. This study employed MTT, wound-healing, colony-formation, Transwell, and xenograft mouse models to demonstrate that CyM effectively suppresses RCC cell proliferation and migration. To figure out the possible mechanism, untargeted metabolomic and transcriptomic analyses found CyM induced ferroptosis by disrupting the cellular oxidative defense system. Subsequent experiments confirmed key ferroptotic events, including increased lipid peroxidation, accumulation of intracellular Fe²⁺, depletion of glutathione, and mitochondrial dysfunction. Ferroptosis inhibitor Ferrostatin-1 (Fer-1) reversed these events, underscoring the central role of ferroptosis in its anti-tumor activity. In summary, this study first demonstrates that CyM exerts anti-RCC effects by triggering ferroptosis through impairment of the oxidative defense system, induction of mitochondrial damage, and lipid peroxidation. These findings identify a promising therapeutic candidate for RCC.