2. Academic Validation
  3. Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke

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

  • Nat Metab. 2025 Sep 23. doi: 10.1038/s42255-025-01379-7.
Qiang Zhao 1,  Jiajian Li 1,  Jingjing Feng 1,  Xin Wang 1,  Yueting Liu 1,  Fei Wang 1,  Liang Liu 1,  Bingxue Jin 1,  Ming Lin 1,  Ya-Chao Wang 2,  Xiuhua Guo 3,  Jieli Chen 4,  Junwei Hao 5 6 7
Affiliations

Affiliations

  • 1 Department of Neurology, Xuanwu Hospital Capital Medical University, National Center for Neurological Disorders, Beijing, China.
  • 2 Department of Neurosurgery, The Institute of Translational Medicine, Shenzhen Second People's Hospital/The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
  • 3 Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing, China.
  • 4 Department of Neurology, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin, China.
  • 5 Department of Neurology, Xuanwu Hospital Capital Medical University, National Center for Neurological Disorders, Beijing, China. haojunwei@vip.163.com.
  • 6 Beijing Municipal Geriatric Medical Research Center, Beijing, China. haojunwei@vip.163.com.
  • 7 Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, China. haojunwei@vip.163.com.
PMID: 40987840 DOI: 10.1038/s42255-025-01379-7
Abstract

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.

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