Omega-3 polyunsaturated fatty acids protect against cisplatin-induced nephrotoxicity by activating the Nrf2 signaling pathway.

Nephrotoxicity is a prevalent side effect observed in patients undergoing chemotherapy. The pathogenesis of chemotherapy-induced nephrotoxicity involves various factors such as oxidative stress, DNA damage, inflammation, and apoptosis. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), possess anti-inflammatory and antioxidant properties. This study investigated the effects of EPA and DHA, either alone or in combination, on cisplatin-induced nephrotoxicity in mice, as well as their underlying mechanisms of action. The combined administration of EPA and DHA demonstrated superior efficacy in mitigating cisplatin-induced nephrotoxicity compared to administration alone, including the reduction of oxidative damage, inflammation, and apoptosis. Moreover, the combination of EPA and DHA suppressed inflammation and prevented the development of chronic kidney fibrosis during prolonged observations following repeated cisplatin administration. Mechanistically, ω-3 PUFAs enhance the expression of antioxidant genes by activating the p62-Keap1-Nrf2 signaling pathway. Furthermore, Nrf2 activation can inhibit the cisplatin-induced p53 apoptosis signal by upregulating the expression of MDM2 in renal tubular epithelial cells. Consequently, ω-3 PUFAs exert a protective effect against cisplatin-induced renal injury through activating the Nrf2 signaling pathway, suggesting that ω-3 PUFAs intake holds promise as a therapeutic strategy for combating cisplatin-induced nephrotoxicity.