Jiang Shuxia, Shu Yujia, Guo Shihui, Ni Yingdong, Zhao Ruqian, Shan Hongli, Ma Wenqiang
Shanghai Frontiers Science Research Center for Druggability of Cardiovascular Noncoding RNA, Institute for Frontier Medical Technology, School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, China.
Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
Int J Mol Sci. 2025 May 16;26(10):4774. doi: 10.3390/ijms26104774.
Excessive iron accumulation poses a significant threat to liver health, primarily through oxidative stress and autophagy dysregulation. α-Lipoic acid (ALA), a natural antioxidant with hepatoprotective properties, may alleviate iron-induced liver damage, but its underlying mechanisms are not fully understood. This study utilized male Sprague Dawley rats and BRL-3A cells to explore the protective effects of ALA against iron overload in vivo and in vitro, respectively. ALA treatment significantly reduced hepatic iron accumulation, improved liver morphology, and alleviated iron-induced ultrastructural damage in rats. ALA also improved liver function markers in plasma, including alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), total bilirubin (TBIL), and the AST/ALT ratio. Furthermore, ALA mitigated iron-induced oxidative stress by lowering hepatic reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing the antioxidant enzyme activities of glutathione peroxidase (GSH-Px) and catalase (CAT). In BRL-3A cells, ALA improved cell viability, decreased intracellular ROS, and reduced iron levels. Proteomics analysis indicates that NAD(P)H: quinone oxidoreductase 1 (NQO1) may play a critical role in the protective effects of ALA against iron overload-induced hepatic damage in rats. Mechanistically, ALA upregulated NQO1 expression while downregulating autophagy-related proteins, including light chain 3B (LC3B), lysosomal-associated membrane protein 1 (LAMP1), and cathepsin D (CTSD). Inhibition or knockdown of NQO1 abolished ALA's protective effects, confirming its role in reducing oxidative stress and excessive autophagy. These findings highlight the potential of ALA as a therapeutic agent for managing hepatic iron toxicity through iron chelation and activation of NQO1.
过量的铁积累对肝脏健康构成重大威胁，主要通过氧化应激和自噬失调。α-硫辛酸（ALA）是一种具有肝脏保护特性的天然抗氧化剂，可能减轻铁诱导的肝损伤，但其潜在机制尚未完全明确。本研究分别利用雄性Sprague Dawley大鼠和BRL-3A细胞，探讨ALA在体内和体外对铁过载的保护作用。ALA治疗显著降低了大鼠肝脏中的铁积累，改善了肝脏形态，并减轻了铁诱导的超微结构损伤。ALA还改善了血浆中的肝功能指标，包括碱性磷酸酶（ALP）、γ-谷氨酰转移酶（GGT）、总胆红素（TBIL）以及AST/ALT比值。此外，ALA通过降低肝脏活性氧（ROS）和丙二醛（MDA）减轻了铁诱导的氧化应激，同时提高了谷胱甘肽过氧化物酶（GSH-Px）和过氧化氢酶（CAT）的抗氧化酶活性。在BRL-3A细胞中，ALA提高了细胞活力，降低了细胞内ROS水平，并降低了铁含量。蛋白质组学分析表明，NAD（P）H：醌氧化还原酶1（NQO1）可能在ALA对大鼠铁过载诱导的肝损伤的保护作用中起关键作用。机制上，ALA上调NQO1表达，同时下调自噬相关蛋白，包括轻链3B（LC3B）、溶酶体相关膜蛋白1（LAMP1）和组织蛋白酶D（CTSD）。抑制或敲低NQO1消除了ALA的保护作用，证实了其在减轻氧化应激和过度自噬中的作用。这些发现凸显了ALA作为一种治疗药物通过铁螯合和激活NQO1来管理肝脏铁毒性的潜力。
