Abstract

Resveratrol (Res), a natural polyphenol, is widely used as a functional food additive and food preservative due to its antioxidant and anti-inflammatory properties. However, its protective role against drug-induced organ damage, particularly colistin-induced nephrotoxicity (CIN), remains underexplored. This study investigated Res's protective effects and mechanisms against CIN in rat and NRK-52E cells. In vivo , Res (5-20 mg/kg) significantly improved renal function, alleviated histopathological damage, and restored antioxidant status. Mechanistically, Res modulated the Keap1/Nrf2 axis, suppressing excessive Nrf2 activation and its downstream enzymes. Concurrently, Res inhibited ferroptosis by reducing iron accumulation and modulating key ferroptosis markers (GPX4, ACSL4). In vitro , Res (20 μM) reversed CS- and RSL3-induced cytotoxicity, lipid peroxidation, and ferrous iron overload; Nrf2 siRNA abrogated these effects, confirming Nrf2's essential role. These findings highlight Res as a promising strategy to enhance colistin's clinical safety through precise Nrf2 modulation and ferroptosis inhibition, underscoring the therapeutic potential of natural food compounds.