Fenofibrate attenuates cisplatin-induced nephrotoxicity in rats by restoring mitochondrial dynamics and improving fatty acid oxidation.

Cisplatin is a standard chemotherapeutic agent widely used for the treatment of common solid tumors; however, its dose-dependent nephrotoxicity severely limits its clinical application. Currently, effective and specific strategies for preventing or reversing cisplatin-induced nephrotoxicity remain limited. Fenofibrate, a clinically used selective PPARα agonist, has shown renoprotective effects in multiple kidney injury models. This study investigated whether fenofibrate attenuates cisplatin-induced nephrotoxicity in rats and explored the underlying mechanisms. Our results showed that cisplatin significantly induces renal injury, along with renal oxidative stress, apoptosis, mitochondrial dynamics imbalance, as well as impaired fatty acid oxidation. However, fenofibrate treatment significantly reduced cisplatin-induced elevations in serum BUN and SCr levels, decreased NGAL and Kim1 expression, and ameliorated renal histopathological damage. Mechanistically, fenofibrate restored mitochondrial homeostasis in the kidney by downregulating Drp1 and upregulating Mfn1, Mfn2, and OPA1. It also alleviated renal oxidative stress, as evidenced by increased GSH and SOD levels and decreased MDA levels, and inhibited renal apoptosis by reducing the expression of Bax and Cleaved Caspase3 while increasing Bcl2 expression. Furthermore, fenofibrate activated the AMPK/PGC-1α/PPARα pathway, suppressed the aberrant upregulation of the fatty acid transporters CD36 and FATP4, and restored the expression of key fatty acid oxidation-related enzymes, including CPT1A, CPT2, and ACOX1. Taken together, these findings suggest that fenofibrate protects against cisplatin-induced nephrotoxicity by restoring mitochondrial dynamics and improving renal fatty acid oxidation.