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：2026 · DOI：10.1021/ehp.6c00267 · 被引用次数：3 · 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 to explore the potential mechanisms. METHODS: Male C57BL/6N mice were subjected to a 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 a 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 by elevated markers of ferroptosis including prostaglandin-endoperoxide synthase 2 (Ptgs2), malond...