Wang Song-Jun, Lu Chao-Long, Zhang Fu, Dong Xue-Tong, Su Xiao-Rui, Sha Jing-Jing, Cong Bin, Liu Xia
Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, College of Forensic Medicine, Hebei Medical University, No. 361 Zhong Shan Road, Shijiazhuang, Hebei, China.
Forensic Pathology Lab, Guangdong Public Security Department, No. 97 Huanghua Road, Guangzhou, 510050, China.
Cell Mol Biol Lett. 2025 Jul 21;30(1):87. doi: 10.1186/s11658-025-00772-0.
Abnormal climate change seriously endangers the safety of outdoor work and life, often causing hypothermia-induced coma or death. As the underlying mechanism has not been fully elucidated, a targeted treatment for hypothermia-triggered neuronal injury and forensic pathology indicators of fatal hypothermia are lacking. Herein, we aimed to explore hypothermia-induced changes in gene expression and metabolite profiles of cerebral cortical tissues to elucidate the mechanism of hypothermia-promoted necroptosis of cerebral cortical neurons. Flow cytometry and fluoro-jade C staining showed that low temperature caused necroptosis of cerebral cortical neurons. Transcriptomics identified 244 differential genes between hypothermia-exposed cortical tissue and control tissue. These genes were enriched in tumor necrosis factor (TNF)-α and nuclear factor (NF)-kappa B signaling pathways, as revealed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Broadly targeted metabolomics identified 49 differential metabolites with significant differences. N-alpha-acetyl-L-arginine, argininosuccinic acid, glutaric acid, and other ornithine cycle-associated metabolites were significantly reduced in the hypothermia-exposed cortical tissue, driving fumaric acid reduction in the tricarboxylic acid (TCA) cycle. In addition, KEGG enrichment analysis showed significant changes in the TCA cycle pathway. A combined transcriptomic and metabolomic analysis uncovered that hypothermia induced oxidative stress through NF-κB activation, caused mitochondrial damage, impaired the ornithine cycle, and, ultimately, induced neuronal necroptosis. Pharmacological inhibition of NF-κB by the SC75741 inhibitor effectively ameliorated hypothermia-triggered necroptosis. In conclusion, our results suggest that the NF-κB transcription factor is a potential marker of hypothermia-induced neuronal necroptosis in the mouse cerebral cortex. In addition, our findings indicate the mechanism of necroptosis in cerebral cortical neurons caused by low temperature, which is beneficial for our understanding of hypothermia-induced coma and death.
异常气候变化严重危及户外工作和生活安全，常导致低温性昏迷或死亡。由于其潜在机制尚未完全阐明，缺乏针对低温引发的神经元损伤的靶向治疗方法以及低温致死的法医学病理指标。在此，我们旨在探究低温诱导的大脑皮质组织基因表达和代谢物谱变化，以阐明低温促进大脑皮质神经元坏死性凋亡的机制。流式细胞术和荧光玉髓C染色显示，低温导致大脑皮质神经元坏死性凋亡。转录组学鉴定出低温暴露的皮质组织与对照组织之间有244个差异基因。京都基因与基因组百科全书（KEGG）通路富集分析显示，这些基因富集于肿瘤坏死因子（TNF）-α和核因子（NF）-κB信号通路。广泛靶向代谢组学鉴定出49种有显著差异的差异代谢物。低温暴露的皮质组织中，N-α-乙酰-L-精氨酸、精氨琥珀酸、戊二酸和其他与鸟氨酸循环相关的代谢物显著减少，导致三羧酸（TCA）循环中的富马酸减少。此外，KEGG富集分析显示TCA循环通路有显著变化。转录组学和代谢组学联合分析发现，低温通过激活NF-κB诱导氧化应激，导致线粒体损伤，损害鸟氨酸循环，并最终诱导神经元坏死性凋亡。SC75741抑制剂对NF-κB的药理抑制有效改善了低温引发的坏死性凋亡。总之，我们的结果表明，NF-κB转录因子是小鼠大脑皮质中低温诱导神经元坏死性凋亡的潜在标志物。此外，我们的研究结果揭示了低温导致大脑皮质神经元坏死性凋亡的机制，这有助于我们理解低温诱导的昏迷和死亡。
