Zhang Jimeng, Luo Yaowen, Xie Changcai, Zhang Min, Qin Heyao, Zhou Yuefei, Wu Xiuquan, Hu Chenchen, Hu Feiming, Fei Xiaowei, Zhang Hongchen, Li Juan, Fu Yihao, Yuan Yunchao, Yang Shuya, Gao Dakuan
Department of Neurosurgery, Xijing Hospital, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China.
Department of Cell Biology, National Translational Science Center for Molecular Medicine, Air Force Military Medical University, Xi'an, Shaanxi, 710032, China.
Redox Biol. 2026 Feb;89:103954. doi: 10.1016/j.redox.2025.103954. Epub 2025 Nov 29.
Phosphoglycerate dehydrogenase (PHGDH) is a key molecule in the progression of Alzheimer's disease. Herein, we report that PHGDH exerts a significant influence on cerebral ischemia-reperfusion injury (CIRI). Ischemia-reperfusion injury is predominantly triggered by oxidative stress and inflammatory responses; however, the underlying molecular mechanisms remain incompletely understood. Our findings demonstrate that PHGDH displays predominant expression in brain astrocytes and undergoes time-dependent alterations in reactive astrocytes following cerebral ischemia-reperfusion. Specifically, targeted knockdown of PHGDH expression in astrocytes substantially exacerbates pathological damage and neurological deficits post cerebral ischemia-reperfusion. Subsequent mechanistic analyses unveiled that PHGDH knockdown predominantly facilitates astrocyte pyroptosis and neuroinflammation. Specifically, downregulation of PHGDH in astrocytes induces oxidative stress, augments ROS production, and diminishes antioxidant levels of GSH and NADPH. Moreover, PHGDH downregulation disrupts the mitochondrial respiratory chain, triggering mitochondrial damage and dsDNA release during ischemia-reperfusion, thereby exacerbating oxidative stress. Collectively, these mechanisms culminate in AIM2 inflammasome activation, as evidenced by substantial increases in AIM2, ASC, and Cleaved Caspase-1 expression. Notably, exogenous depletion of serine and glycine fails to fully explain the astrocyte pyroptosis triggered by PHGDH knockdown. In conclusion, downregulation of PHGDH in astrocytes post cerebral ischemia-reperfusion predominantly drives astrocyte pyroptosis via oxidative stress, resulting in the release of pro-inflammatory cytokines (e.g., IL-1β and IL-18) and subsequent exacerbation of ischemia-reperfusion injury. These novel insights into the role of PHGDH may inform the development of targeted therapeutic strategies for cerebral ischemia-reperfusion.
磷酸甘油酸脱氢酶（PHGDH）是阿尔茨海默病进展中的关键分子。在此，我们报告PHGDH对脑缺血再灌注损伤（CIRI）有显著影响。缺血再灌注损伤主要由氧化应激和炎症反应引发；然而，其潜在的分子机制仍未完全明确。我们的研究结果表明，PHGDH在脑星形胶质细胞中呈优势表达，并且在脑缺血再灌注后反应性星形胶质细胞中会发生时间依赖性改变。具体而言，星形胶质细胞中PHGDH表达的靶向敲低显著加剧了脑缺血再灌注后的病理损伤和神经功能缺损。随后的机制分析揭示，PHGDH敲低主要促进星形胶质细胞焦亡和神经炎症。具体来说，星形胶质细胞中PHGDH的下调诱导氧化应激，增加活性氧生成，并降低谷胱甘肽（GSH）和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的抗氧化水平。此外，PHGDH下调破坏线粒体呼吸链，在缺血再灌注期间引发线粒体损伤和双链DNA释放，从而加剧氧化应激。总的来说，这些机制最终导致AIM2炎性小体激活，这可通过AIM2、凋亡相关斑点样蛋白（ASC）和裂解的半胱天冬酶 -1表达的显著增加得到证明。值得注意的是，丝氨酸和甘氨酸的外源性消耗并不能完全解释PHGDH敲低引发的星形胶质细胞焦亡。总之，脑缺血再灌注后星形胶质细胞中PHGDH的下调主要通过氧化应激驱动星形胶质细胞焦亡，导致促炎细胞因子（如白细胞介素 -1β和白细胞介素 -18）的释放以及随后缺血再灌注损伤的加剧。这些关于PHGDH作用的新见解可能为脑缺血再灌注的靶向治疗策略的开发提供信息。
