Loganin triggers ferroptosis in renal cell carcinoma by targeting the IGF2BP2/HMOX1 axis in an m6A-dependent manner.

Renal cell carcinoma (RCC) remains a clinical challenge due to its high metastatic potential and resistance to conventional therapies. Loganin (LGN), a bioactive iridoid glycoside, has shown promise in various diseases, yet its role in RCC remains poorly understood. In this study, we demonstrate that LGN significantly inhibits the proliferation and metastasis of RCC cells both in vitro and in vivo while exhibiting minimal toxicity toward normal renal cells. Mechanistically, we identify IGF2BP2 as a direct functional target of LGN. Biotin-pulldown and Microscale Thermophoresis (MST) assays confirm that LGN physically binds to IGF2BP2, leading to its protein destabilization and degradation. This downregulation of IGF2BP2 subsequently impairs its m6A-dependent regulation of HMOX1 mRNA, resulting in the marked upregulation of HMOX1. The resulting HMOX1 induction triggers catastrophic ferroptosis, characterized by intracellular iron overload, glutathione depletion, and lethal lipid peroxidation. Furthermore, LGN synergistically enhances the anti-tumor efficacy of the ferroptosis inducer RSL3. Collectively, our findings elucidate the LGN/IGF2BP2/HMOX1 axis as a critical regulatory node in RCC ferroptosis and position Loganin as a potential therapeutic candidate for the treatment of advanced renal cell carcinoma.