Liu Zuolong, Sun Lanyue, Gao Nan, Li Wei, Pang Li
Department of Emergency, The First Hospital of Jilin University, No. 1 Xinmin Road, Changchun, Jilin Province, 130021, P.R. China.
Medical Quality Control Office, The Third Affiliated Hospital of Changchun, University of Chinese Medicine, Changchun, Jilin Province, 130118, P.R. China.
Acta Neuropathol Commun. 2025 Jul 14;13(1):154. doi: 10.1186/s40478-025-02069-x.
Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is the most common complication after acute carbon monoxide (CO) poisoning. However, the pathogenesis of DEACMP remains ambiguous. The neuroprotective role of GPNMB has been observed in amyotrophic lateral sclerosis and Parkinson's disease. GPNMB was elevated in the brain tissues of DEACMP rats, while its function in DEACMP remains unclear. In this study, a CO poisoning rat model and oxygen-glucose deprivation (OGD)-treated PC-12 cells were established as an in vivo and in vitro DEACMP model, respectively. The ferroptosis inhibitor Ferrostatin-1 (Fer-1) ameliorated cognitive impairment, inflammation and oxidative stress of rats with DEACMP as assessed by Morris Water Maze test, ELISA assay and commercial kits of oxidative markers. Immunofluorescence, qRT-PCR or western blot showed that GPNMB was elevated in CA1 hippocampal tissues of CO-poisoned rats. Additionally, TUNEL staining, ELISA assay and western blot revealed that GPNMB rescued OGD-induced cell apoptosis, inflammation and ferroptosis in PC-12 cells. Mechanistical study showed that STAT3 was a transcriptional activator of GPNMB as detected by luciferase and ChIP assays, and co-immunoprecipitation and immunofluorescence staining revealed that GPNMB stabilized HIF-1α by direct binding. Functionally, GPNMB protected against OGD-induced impairments via inducing HIF-1α. Furthermore, GPNMB attenuated cognitive impairment, oxidative stress and neuronal ferroptosis of rats with DEACMP. In conclusion, GPNMB/HIF-1α exhibited neuroprotective effects via suppressing ferroptosis in DEACMP.
急性一氧化碳中毒后迟发性脑病（DEACMP）是急性一氧化碳（CO）中毒后最常见的并发症。然而，DEACMP的发病机制仍不明确。在肌萎缩侧索硬化症和帕金森病中已观察到GPNMB的神经保护作用。GPNMB在DEACMP大鼠的脑组织中升高，但其在DEACMP中的功能仍不清楚。在本研究中，分别建立了CO中毒大鼠模型和氧糖剥夺（OGD）处理的PC-12细胞作为体内和体外DEACMP模型。通过莫里斯水迷宫试验、ELISA检测和氧化标志物商业试剂盒评估，铁死亡抑制剂Ferrostatin-1（Fer-1）改善了DEACMP大鼠的认知障碍、炎症和氧化应激。免疫荧光、qRT-PCR或蛋白质印迹显示，GPNMB在CO中毒大鼠的海马CA1组织中升高。此外，TUNEL染色、ELISA检测和蛋白质印迹显示，GPNMB挽救了OGD诱导的PC-12细胞凋亡、炎症和铁死亡。机制研究表明，荧光素酶和染色质免疫沉淀试验检测到STAT3是GPNMB的转录激活因子，免疫共沉淀和免疫荧光染色显示GPNMB通过直接结合稳定HIF-1α。在功能上，GPNMB通过诱导HIF-1α保护细胞免受OGD诱导的损伤。此外，GPNMB减轻了DEACMP大鼠的认知障碍、氧化应激和神经元铁死亡。总之，GPNMB/HIF-1α通过抑制DEACMP中的铁死亡发挥神经保护作用。
