Zhao Yonggang, Tuo Wei, Wu Xiaomin, Gou Ruoyu, Hou Ling, Liu Juan, Li Guanghua
School of Public Health, Ningxia Medical University, Yinchuan, China.
Department of Children's Neurorehabilitation, Hospital of Ningxia Hui Autonomous Region, Yinchuan, China.
Shock. 2025 Aug 1;64(2):272-282. doi: 10.1097/SHK.0000000000002625. Epub 2025 May 20.
As the frequency of global heat waves keeps rising, exertional heat stroke (EHS) is becoming an increasingly prevalent health concern, which causes myocardial injury. However, the mechanisms underlying myocardial injury following EHS are still unclear. In this study, we established an EHS mouse model in which mice were exercised by running on a treadmill in a high-humidity and high-temperature environment and investigated the time points of myocardial injury within 24 h after EHS. We found that mice had cardiac dysfunction and myocardial injury after EHS and that the damage was the most serious at 6 h of recovery. Next, changes in cardiac ferroptosis and lipid peroxidation levels after EHS were evaluated, and ferroptosis was found to be the main form of myocardial cell death, and inhibition of ferroptosis by liproxstatin-1 ameliorated EHS-induced myocardial injury. In addition, we found that arachidonic acid 15-lipoxygenase-1 (Alox15) is a critical molecule of ferroptosis in cardiomyocytes through targeted metabolomics experiments. Based on in vivo and in vitro studies, inhibiting Alox15 conspicuously ameliorates EHS-induced cardiac dysfunction and myocardial injury. Mechanistically, EHS-induced excessive activation of transcription factor p53 upregulated Alox15 expression via inducing SAT1 (spermidine/spermine N1-acetyltransferase 1) expression and reduced the expression of Gpx4 (glutathione peroxidase 4) to initiate ferroptosis. This study reveals the key role of ferroptosis in EHS-induced myocardial injury and confirms that Alox15-mediated ferroptosis of cardiomyocytes is the core pathological mechanism. This finding provides a new molecular target and theoretical basis for the prevention and treatment strategies of EHS-related myocardial injury.
随着全球热浪发生频率不断上升，劳力性热射病（EHS）正成为一个日益普遍的健康问题，它会导致心肌损伤。然而，EHS后心肌损伤的潜在机制仍不清楚。在本研究中，我们建立了一个EHS小鼠模型，让小鼠在高湿度和高温环境下在跑步机上跑步进行运动，并研究了EHS后24小时内心肌损伤的时间点。我们发现，EHS后小鼠出现心脏功能障碍和心肌损伤，且在恢复6小时时损伤最为严重。接下来，评估了EHS后心脏铁死亡和脂质过氧化水平的变化，发现铁死亡是心肌细胞死亡的主要形式，liproxstatin-1抑制铁死亡可改善EHS诱导的心肌损伤。此外，通过靶向代谢组学实验，我们发现花生四烯酸15-脂氧合酶-1（Alox15）是心肌细胞铁死亡的关键分子。基于体内和体外研究，抑制Alox15可显著改善EHS诱导的心脏功能障碍和心肌损伤。机制上，EHS诱导转录因子p53过度激活，通过诱导SAT1（亚精胺/精胺N1-乙酰转移酶1）表达上调Alox15表达，并降低Gpx4（谷胱甘肽过氧化物酶4）表达以启动铁死亡。本研究揭示了铁死亡在EHS诱导的心肌损伤中的关键作用，并证实Alox15介导的心肌细胞铁死亡是核心病理机制。这一发现为EHS相关心肌损伤的预防和治疗策略提供了新的分子靶点和理论基础。
