Docosahexaenoic acid attenuates cisplatin nephrotoxicity by restoring mitophagy

Cisplatin exhibits potent antitumor efficacy but also causes dose-dependent nephrotoxicity mediated through apoptosis of renal tubular epithelial cells, which limits its clinical application. Cisplatin induces significant mitophagy in these cells; however, the mechanisms underlying its effects on apoptotic processes remain incompletely elucidated. This study investigated the mechanism by which the polyunsaturated fatty acid docosahexaenoic acid (DHA) modulates mitophagy to alleviate cisplatin nephrotoxicity. A cisplatin-induced (15 mg/kg, intraperitoneal) acute kidney injury model was established in C57BL/6J mice, with the intervention group receiving albumin-conjugated DHA (4 mg/kg). Systematic analyses revealed that cisplatin perturbed lysosomal degradation, which led to accumulation of dysfunctional mitochondria and increased apoptosis due to impaired mitophagic flux. DHA ameliorated lysosomal dysfunction, enhanced clearance of dysfunctional mitochondria, and suppressed apoptosis. Our findings suggest that blockade of mitophagic flux is a pivotal mechanism underlying cisplatin nephrotoxicity and that DHA-mediated restoration of mitophagy is a promising therapeutic strategy.