Echinacoside Alleviates Cisplatin-Induced Acute Kidney Injury by Regulating Bap1 to Inhibit Ferroptosis.

Background/Objectives: Cisplatin-induced acute kidney injury (AKI) is a major adverse complication restricting cisplatin-based chemotherapy. Ferroptosis contributes substantially to proximal tubular epithelial injury during AKI. This work aimed to explore the renoprotective effect of echinacoside (ECH) and its underlying molecular mechanism against cisplatin-provoked AKI. Methods: Eight-week-old male C57BL/6 cisplatin-AKI mice models and HK-2 tubular epithelial cells were used for in vivo and in vitro experiments. Public single-cell transcriptome data and 4D-DIA proteomics were applied to screen key ferroptosis-associated molecules. Functional validation, Western blotting, and molecular docking simulations were performed to characterize the regulatory axis of ECH. Results: ECH ameliorated renal dysfunction, inflammation, and tubular damage in cisplatin-induced AKI. Omics analyses nominated Bap1 as a critical ferroptosis-related differential protein. ECH restored the Slc7a11/GPX4 pathway to restrain lipid peroxidation and mitochondrial ferroptotic damage. Molecular docking predicted a potential interaction between ECH and Bap1. ECH downregulated Bap1 protein expression, and Bap1 overexpression largely abrogated ECH-mediated anti-ferroptosis and renoprotective effects. Conclusions: ECH mitigates cisplatin-triggered AKI, which is associated with Bap1 downregulation, Slc7a11/GPX4 axis restoration, and ferroptosis suppression. The ECH-Bap1-ferroptosis regulatory relationship offers a candidate therapeutic target and natural agent for the preventive treatment of cisplatin-related nephrotoxicity.