Icaritin Ameliorates Cisplatin‐Induced Mitochondrial Metabolic Dysfunction‐Associated Nephrotoxicity and Synergistically Potentiates Its Antitumor Efficacy

Abstract Cisplatin (CDDP) is a highly effective chemotherapy drug with broad clinical utility. Yet its therapeutic application is significantly constrained by off‐target toxicities, especially nephrotoxicity. However, the molecular mechanisms underlying CDDP‐induced kidney injury remain incompletely elucidated. Here, integrated multi‐omics approaches are employed to dissect the pathophysiology of CDDP nephrotoxicity and uncover that CDDP directly binds to mitochondrial proteins, causing metabolic dysfunction and impairing mitochondrial respiration. Additionally, CDDP triggers mitochondrial reactive oxygen species generation, activating the nuclear factor kappa‐B (NF‐κB) signaling pathway and downstream inflammatory effectors. scRNA‐seq analysis reveals remarkable cellular heterogeneity in the renal response to CDDP exposure. Mechanistically, it is identified that CDDP‐bound proteins are predominantly localized in proximal tubular (PT) cells. Ligand–receptor analysis demonstrates that CDDP‐damaged PT cells recruit and activate renal immune cells in tumor‐bearing mice, exacerbating renal injury. Notably, icaritin (ICA) effectively mitigates CDDP‐induced reactive oxygen species (ROS) accumulation, suppresses NF‐κB activation and inflammation, and restores metabolic homeostasis. Combinatorial treatment with ICA not only ameliorates CDDP‐induced nephrotoxicity but also enhances its anti‐cancer efficacy. Taken together, these findings provide novel mechanistic insights into CDDP nephrotoxicity and propose a dual‐function therapeutic strategy to optimize CDDP‐based cancer therapy while minimizing renal damage.