Hu Zhisheng, Hao Weihua, Dai Wenqing, Gao Xin, Cui Na, Wang Minge, Fang Liangxing, Sun Jian, Zhang Hongyan, Liao Xiaoping
Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou 510642, China.
J Agric Food Chem. 2025 Jun 18;73(24):15281-15295. doi: 10.1021/acs.jafc.4c13030. Epub 2025 Jun 5.
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. , 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. 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-mediated lipid peroxidation inhibition and mitochondrial protection, highlighting the targeted activation of the Nrf2-GPX4 axis as a promising therapeutic strategy to mitigate renal damage.
黏菌素（CS）诱导的肾毒性仍然是一个重大的临床挑战，其机制尚未完全明确。本研究旨在探究铁死亡及核因子红细胞2相关因子2（Nrf2）抗氧化途径在CS诱导的肾损伤中的作用。用CS处理的大鼠表现出肾损伤，其特征为血清血尿素氮（BUN）和肌酐水平升高、生物标志物（肾损伤分子-1（Kim-1）和中性粒细胞明胶酶相关脂质运载蛋白（NGAL））增加，以及肾小管损伤的组织病理学证据。观察到氧化应激，其特征为抗氧化酶活性（过氧化氢酶（CAT）、超氧化物歧化酶（SOD）和谷胱甘肽（GSH））降低以及丙二醛（MDA）水平升高。此外，CS激活了肾组织中的Nrf2途径。观察到铁死亡标志物，包括铁沉积、线粒体损伤以及铁死亡相关蛋白（酰基辅酶A合成酶长链家族成员4（ACSL4）、铁蛋白重链1（FTH1）和谷胱甘肽过氧化物酶4（GPX4））表达改变。对NRK-52E细胞的研究证实了这些发现，包括线粒体功能障碍和动力学破坏（有利于裂变）。铁死亡抑制剂1减轻了细胞毒性，而Nrf2基因敲低加剧了氧化应激、线粒体功能障碍和铁死亡。这些发现表明，Nrf2通过抑制GPX4介导的脂质过氧化和线粒体保护来减轻黏菌素诱导的肾毒性，突出了靶向激活Nrf2-GPX4轴作为减轻肾损伤的一种有前景的治疗策略。
