Alpha-linolenic acid protects against heatstroke-induced acute lung injury by inhibiting ferroptosis through Nrf2 activation

Heatstroke (HS)-induced acute lung injury (ALI) has high morbidity and mortality with no specific therapies. Ferroptosis, a form of programmed cell death driven by lipid peroxidation due to reduced Glutathione Peroxidase 4 (GPX4) activity, is closely linked to HS-induced ALI. This study investigated the effect of alpha-linolenic acid (ALA), a plant-derived ω-3 fatty acid, on ferroptosis in a mouse model of HS-induced ALI. Histopathology analysis found that ALA can attenuate lung injury and improve the 7-day survival rate in mice with HS-induced ALI. In addition, ALA significantly reduced the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing the level of antioxidant glutathione (GSH). Further analysis showed that ALA upregulated the levels of SLC7A11 and GPX4 by promoting the nuclear translocation of Nrf2. This led to increased GSH synthesis but reduced ROS accumulation, which in turn suppressed ferroptosis and protected the mice against HS-induced ALI. Additionally, the protective effect of ALA was found to be diminished in <i>Nrf2</i>-deficient mice. In summary, ALA inhibits ferroptosis in macrophages by activating the Nrf2/SLC7A11/GPX4 pathway and attenuates HS-induced ALI.

热射病（Heatstroke, HS）诱发的急性肺损伤（acute lung injury, ALI）发病率与死亡率居高不下，且尚无针对性治疗手段。铁死亡（Ferroptosis）是一种因谷胱甘肽过氧化物酶4（Glutathione Peroxidase 4, GPX4）活性降低引发脂质过氧化所驱动的程序性细胞死亡形式，与热射病诱发的急性肺损伤密切相关。本研究探究了植物来源的ω-3脂肪酸α-亚麻酸（alpha-linolenic acid, ALA）对热射病诱发急性肺损伤小鼠模型中铁死亡的调控作用。组织病理学分析显示，ALA可减轻热射病诱发急性肺损伤小鼠的肺损伤程度，并提升其7天生存率。此外，ALA可显著降低活性氧（reactive oxygen species, ROS）与丙二醛（malondialdehyde, MDA）水平，同时提升抗氧化物质谷胱甘肽（glutathione, GSH）的含量。进一步分析表明，ALA通过促进核因子E2相关因子2（nuclear factor erythroid 2-related factor 2, Nrf2）的核转位，上调SLC7A11与GPX4的表达水平。这一过程可增强谷胱甘肽合成并减少活性氧积累，进而抑制铁死亡，保护小鼠免受热射病诱发的急性肺损伤。此外，在Nrf2缺陷小鼠中，ALA的保护作用被显著削弱。综上，ALA通过激活Nrf2/SLC7A11/GPX4通路抑制巨噬细胞铁死亡，进而减轻热射病诱发的急性肺损伤。