Folic Acid Ameliorates Neuronal Ferroptosis in Aging by Up-Regulating SLC7A11-GSH-GPX4 Antioxidant Pathway and Increasing Cystine Levels

作者：Yue Wang, Jingwen Zhang, Zehao Wang, Qinghan Ren, Zhenshu Li, Guo-Wei Huang, Li Wen · 发表于：International Journal of Molecular Sciences · 年份：2025 · DOI：10.3390/ijms26146669 · 被引用次数：10 · 研究领域：Ferroptosis and cancer prognosis、Cancer-related molecular mechanisms research、RNA modifications and cancer

Age-related neurodegeneration is characterized by oxidative stress and iron-dependent cell death, yet the neuroprotective mechanisms of folic acid in modulating ferroptosis remain unclear. This study systematically investigated the role of folic acid in inhibiting ferroptosis and attenuating neuronal damage in aging, with a focus on the solute carrier family 7 member 11 (SLC7A11)-glutathione (GSH)-glutathione peroxidase 4 (GPX4) antioxidant pathway, using aged rats supplemented with folic acid (<0.1, 2.0, and 4.0 mg/kg·diet) for 22 months, with young adult rats as controls. Brain iron accumulation and ferroptosis-related proteins (SLC7A11, GPX4, Ferritin heavy chain 1 (FTH1)) were evaluated. In vitro, HT-22 hippocampal neuronal cells were pre-treated with folic acid (0, 10, 20 μmol/L) for 72 h before combining with Erastin (10 μmol/L)-induced ferroptosis for an additional 24 h. Intracellular Fe2+, lipid peroxidation (LPO), malondialdehyde (MDA), reactive oxygen species (ROS), along with cystine, GSH, and ferroptosis-related protein levels were quantified. Stable sh-SLC7A11 knockdown and control (sh-NC) cell lines were used to validate the dependency of folic acid’s protective effects on SLC7A11 expression. Folic acid supplementation in aged rats dose-dependently reduced aging-related brain iron accumulation and enhanced the expression of SLC7A11, GPX4, and FTH1. In Erastin-induced HT-22 cells, folic acid significantly mitigated ferroptosis hallmarks. Mechanistically, folic...