Nrf2 Alleviates Colistin-Induced Nephrotoxicity by Suppressing Ferroptosis via GPX4-Mediated Lipid Peroxidation and Mitochondrial Protection

作者：Zhisheng Hu, Wei-Hua Hao, Wenqing Dai, Xin Gao, Na Cui, Min-Ge Wang, Liang‐Xing Fang, Jian Sun, Hongyan Zhang, Xiao‐Ping Liao · 发表于：Journal of Agricultural and Food Chemistry · 年份：2025 · DOI：10.1021/acs.jafc.4c13030 · 被引用次数：13 · 研究领域：Ferroptosis and cancer prognosis、Drug Transport and Resistance Mechanisms、Cancer, Lipids, and Metabolism

Colistin (CS)-induced nephrotoxicity remains a major clinical challenge, with its mechanisms not fully understood. This study aimed to investigate the involvement of ferroptosis and the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway in CS-induced kidney damage. In vivo, rats treated with CS exhibited kidney injury, marked by elevated serum blood urea nitrogen (BUN) and creatinine levels, increased biomarkers (kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (NGAL)), and histopathological evidence of tubular damage. Oxidative stress was observed, characterized by reduced antioxidant enzyme activities (catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH)) and increased malondialdehyde (MDA) levels. Additionally, CS activated the Nrf2 pathway in renal tissues. Ferroptosis markers, including iron deposition, mitochondrial damage, and altered expression of ferroptosis-related proteins (Acyl-CoA synthetase long-chain family member 4 (ACSL4), ferritin heavy chain 1 (FTH1), and glutathione peroxidase 4 (GPX4)), were observed. In vitro studies with NRK-52E cells confirmed these findings, including mitochondrial dysfunction and dynamics disruption (favoring fission). Ferrostatin-1 alleviated cytotoxicity, while Nrf2 knockdown exacerbated oxidative stress, mitochondrial dysfunction, and ferroptosis. These findings reveal that Nrf2 alleviates colistin-induced nephrotoxicity by suppressing ferroptosis through the GPX4-med...