CYP2E1 inhibitor Q11 shows potential in alleviating cisplatin-induced acute kidney injury via mitigating...

Cisplatin remains a major cause of acute kidney injury (AKI) and effective therapeutic strategies are still lacking. Cytochrome P450 2E1 (CYP2E1), a phase I metabolic enzyme, has been increasingly implicated in inflammatory disorders. This study aimed to investigate the therapeutic potential and underlying mechanisms of a novel CYP2E1 inhibitor, Q11, in cisplatin-induced AKI. The role of CYP2E1 in AKI was assessed using Cyp2e1 knockout rats, and the protective effects of Q11 were evaluated in a mouse model. Further mechanistic insights were gained through transcriptomic analysis and experiments in renal tubular epithelial cells. The results showed that CYP2E1 expression and enzymatic activity were significantly elevated in AKI animals. Knockout of Cyp2e1 markedly attenuated renal dysfunction and inflammation. Treatment with Q11 similarly improved survival, reduced serum creatinine and blood urea nitrogen levels, and alleviated renal histopathological damage in cisplatin-treated mice. Mechanistically, Q11 suppressed oxidative stress by reducing reactive oxygen species (ROS) and increasing glutathione levels, and also downregulated pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Transcriptomic and western blot analyses revealed that Q11 inhibited the nuclear factor kappa B (NF-κB) signaling pathway and restored mitochondrial function. In vitro studies further demonstrated that Q11 reduced CYP2E1 expression, improved mitochondrial membrane potential, and decreased apoptosis in human kidney-2 cells (HK-2) and mouse renal tubular epithelial cells (mRTEC). In conclusion, CYP2E1 plays a pivotal role in cisplatin-induced AKI, and the novel inhibitor Q11 exerts renoprotective effects by mitigating mitochondrial dysfunction and suppressing NF-κB-mediated inflammation.