Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke

作者：Qiang Zhao, Jianbing Li, Jingjing Feng, Xin Wang, Yueting Liu, Fei Wang, Liang Liu, Bingxue Jin, Ming Lin, Yachao Wang, Xiuhua Guo, Jieli Chen, Junwei Hao · 发表于：Nature Metabolism · 年份：2025 · DOI：10.1038/s42255-025-01379-7 · 被引用次数：55 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Atherosclerosis and Cardiovascular Diseases、Immune cells in cancer

Chronic neuroinflammation is a major obstacle to post-stroke recovery, yet the underlying mechanisms, particularly the link between prolonged microglial activation and cholesterol metabolism, are not fully known. Here we show that ischaemic injury induces persistent microglial activation that perpetuates chronic inflammation, leading to microglial cholesterol accumulation and metabolic reprogramming. Using single-cell RNA sequencing, we identified distinct stroke-associated foamy microglia clusters characterized by extensive reprogramming of cholesterol metabolism. Furthermore, direct intracerebral free cholesterol or cholesterol crystal infusion recapitulated sustained microglial activation, directly linking aberrant cholesterol metabolism to prolonged neuroinflammatory responses. Therapeutically, we demonstrate that reducing microglial cholesterol overload through genetic or pharmacological activation of CYP46A1 in male mice promotes white matter repair and functional recovery. These findings highlight microglial cholesterol metabolism as a key driver of post-stroke inflammation, offering therapeutic strategies targeting cholesterol metabolism to mitigate long-term brain damage and promote neurorestoration, potentially improving stroke-related disability outcomes.