GSTM1 Deficiency Exacerbates Cisplatin-Induced Kidney Injury via Increased Oxidative Stress

Cisplatin, a potent chemotherapeutic agent, is highly effective in various cancers but its use is significantly limited by kidney injury, occurring in approximately 30% of patients. Cisplatin-induced kidney injury compromises optimal dosing, reducing cancer survival, and leads to permanent eGFR decline, increasing chronic kidney disease (CKD) risk and cardiovascular mortality. Increased reactive oxygen species (ROS) generation is central to cisplatin nephrotoxicity. Glutathione-S-transferase Mu-1 (GSTM1), a phase II detoxification enzyme, protects against oxidative stress. A common GSTM1 null deletion variant is highly prevalent in human populations. We hypothesized that GSTM1 deficiency increases susceptibility to cisplatin nephrotoxicity. Using a clinically relevant low-dose, repeat-cycle cisplatin mouse model, we found that cisplatin treatment significantly induces renal Gstm1 expression in wild-type mice, suggesting a protective role. Gstm1 knockout mice exhibited more severe kidney injury, evidenced by elevated creatinine, BUN, KIM-1, 4-HNE adducts, and histological damage. This exacerbated injury was associated with significantly higher renal ROS and NOX2 expression and mitochondrial ROS. In vitro studies using primary mouse proximal tubular cells deficient in Gstm1 and human HK-2 cells endogenously lacking GSTM1 demonstrated that GSTM1 deficiency leads to increased mitochondrial ROS and NOX2 expression following cisplatin treatment; conversely, overexpression of GSTM1 in HK-2 cells significantly attenuated cisplatin-induced mitochondrial ROS and NOX2 expression. Furthermore, GSTM1 protected against NF-κB activation and cell death. Our findings establish GSTM1 as a critical cytoprotective factor against cisplatin nephrotoxicity, mitigating oxidative stress, inflammation, and apoptosis, and identify the highly prevalent GSTM1 null variant as a potential genetic risk factor for cisplatin-induced kidney injury.