Beneficial Effects of Sodium-Glucose Cotransporter 2 Inhibitors in Cisplatin Nephrotoxicity: A Mechanistic Review

Cisplatin remains a key chemotherapy for many solid tumors, but its dose-limiting nephrotoxicity affects up to one third of patients and has no effective pharmacologic prevention beyond hydration and magnesium supplementation. Preclinical studies highlight sodium-glucose cotransporter 2 (SGLT2) inhibitors as promising nephroprotective agents during cisplatin therapy, independent of glucose lowering. We conducted a PubMed search using predefined terms related to cisplatin nephrotoxicity and SGLT2 inhibitors, identifying seven nondiabetic rodent studies. Across these models, SGLT2 inhibitors consistently attenuated kidney injury through complementary mechanisms such as suppression of inflammatory, oxidative, and apoptotic pathways; activation of AMP-activated protein kinase-dependent autophagy; reduction of kidney platinum accumulation; and, uniquely, correction of cisplatin-induced hypomagnesemia, a clinically significant complication. Protective effects occurred without compromising cisplatin's antitumor efficacy in vitro . Overall, these findings support SGLT2 inhibitors as a mechanistically versatile strategy that targets key injury pathways in platinum nephrotoxicity. Although prospective clinical application remains untested, the strong biologic rationale, reproducibility across models, and established safety of SGLT2 inhibitors in other populations underscore the urgency of translation. Future clinical trials should incorporate rigorous assessments of kidney function, tubular injury biomarkers, and urinary extracellular vesicle profiling to define the safety, efficacy, and mechanistic insights of SGLT2 inhibitors in cisplatin nephrotoxicity.