Dihydrotanshinone I attenuates cisplatin-induced acute kidney injury by targeting TRIM28-mediated oxidative stress and apoptosis: insights from activity-based protein profiling and omics integration

Cisplatin, a platinum-based chemotherapeutic agent, is widely used in cancer treatment, but its limitation lies in its nephrotoxicity, which compromises its clinical use. This study investigated the therapeutic potential of dihydrotanshinone I (DHT), a natural diterpene from Salvia miltiorrhiza, in mitigating cisplatin-induced nephrotoxicity via dual antioxidant and antiapoptotic mechanisms. Using activity-based protein profiling, we identified tripartite motif containing 28 (TRIM28) as a direct molecular target of DHT in human proximal tubule epithelial cells. DHT treatment significantly attenuated cisplatin-induced cytotoxicity through TRIM28-mediated reduction of reactive oxygen species (ROS) accumulation and inhibition of apoptotic signaling. Proteomic analysis revealed that DHT restored cisplatin-altered protein expression linked to oxidative stress and apoptosis pathways. Pretreatment with DHT (15 mg kg−1 day−1, oral gavage) in cisplatin-treated C57BL/6 mice preserved the renal function, reduced the acute tubular injury, and reversed the cisplatin-induced oxidative imbalance (enhanced superoxide dismutase activity, reduced malondialdehyde and ROS) and apoptotic signaling (BAX/Bcl-2, c-caspase 3) via in vivo experiments. These findings suggest that DHT is a promising renoprotective adjuvant for platinum-based chemotherapy.