Reciprocal regulation of GPNMB/HIF-1α for Inhibition of neuronal ferroptosis in delayed encephalopathy after acute carbon monoxide poisoning

作者：Zuolong Liu, Lanyue Sun, Nan Gao, Wei Li, Li Pang · 发表于：Acta Neuropathologica Communications · 年份：2025 · DOI：10.1186/s40478-025-02069-x · 被引用次数：6 · 研究领域：Heme Oxygenase-1 and Carbon Monoxide、Ferroptosis and cancer prognosis、Intracerebral and Subarachnoid Hemorrhage Research

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 fer...