PHGDH-dependent serine metabolism in astrocytes: A key regulator of oxidative stress and pyroptosis in cerebral ischemia-reperfusion injury

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.