Effects of extreme heat exposure on heatstroke and liver injury in mice: The role of PPARα.

作者：Guoqing Zhang, Li-Sha Zhao, Jiahui Wang, Kunyi Wang, Xiuyu Ji, Renjie Hu, Tong Hou, Lu Zhang, Ran Li, Qing Sun, Kezhong Zhang, Cui-Qing Liu · 发表于：Environmental Health Perspectives · 年份：2025 · DOI：10.1289/ehp15326 · 研究领域：Medicine

BACKGROUND Liver injury is a frequent complication of heatstroke and constitutes a direct cause of death. However, only a few studies examined the mechanism underlying heatstroke-induced liver injury. OBJECTIVE We aimed to evaluate the role of peroxisome proliferator-activated receptor α (PPARα) in heatstroke-induced liver injury and explore the potential mechanisms. METHODS Male C57BL/6N mice were subjected to control (22 ± 1°C) or extreme heat temperature (39.5 ± 0.5°C) to induce a heatstroke-associated liver injury animal model. PPARα agonist, ferroptosis inhibitor and AAV8-mediated PPARα overexpression were administered to the mice to investigate the role of PPARα and ferroptosis in the heatstroke-induced liver injury. Serum was collected for liver function evaluation. Liver tissues were applied for morphological observation, staining detection, ferroptosis examination and mechanistic exploration. RESULTS Compared with the control group, extreme heat exposure induced temperature dysregulation, impaired liver function and morphological damage in mice. Proteomics screened PPARα as protein of interest, with its level being significantly decreased in response to extreme heat exposure. Both PPARα activation and overexpression attenuated extreme heat-induced heatstroke and liver injury. Hmox1 was next screened and higher Hmox1 expression was identified, accompanied with elevated markers of ferroptosis including prostaglandin-endoperoxide synthase 2 (Ptgs2), malondialdehyd...