Therapeutic Potential of Trilobatin in Cisplatin-Induced Kidney Injury: Targeting Ferroptosis and Inflammation

Abstract Cisplatin-induced acute kidney injury (CI-AKI) is a common and severe complication in cancer patients undergoing chemotherapy, which can progress to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Ferroptosis and inflammation are critical pathological mechanisms underlying CI-AKI. Trilobatin (TLB), a natural product, exhibits significant anticancer, antioxidant, and anti-inflammatory activities. In this study, we investigated the protective effect and molecular mechanism of TLB against CI-AKI through in vitro, in vivo, and network pharmacology experiments. Results from both in vitro and in vivo experiments demonstrated that TLB reversed Erastin-induced ferroptosis and inflammatory responses in human kidney-2 (HK-2) cells, a human renal cortical proximal tubule epithelial cell line. Moreover, TLB significantly ameliorated CI-AKI in model mice in a dose-dependent manner. Mechanistic studies revealed that TLB activated Nrf2 to upregulate the expression of GPX4, thereby alleviating ferroptosis in both HK-2 cells and renal cells of CI-AKI mice. Additionally, TLB effectively reduced the mRNA and protein levels of pro-inflammatory cytokines TNF-α and IL-6 in Erastin-induced HK-2 cells and renal tissues of CI-AKI mice, thus mitigating inflammatory responses. These findings provide a theoretical basis for the clinical application of TLB in the prevention and treatment of CI-AKI.