2. Academic Validation
  3. RetSat Knockout Mitigates Hypoxia-Induced Microglial Activation by Enhancing Lipid Droplets Degradation

RetSat Knockout Mitigates Hypoxia-Induced Microglial Activation by Enhancing Lipid Droplets Degradation

  • Glia. 2026 Feb;74(2):e70118. doi: 10.1002/glia.70118.
Wenyu Hu 1,  Shuoshuo Li 1 2,  Wenjun Shi 1 3,  Ping Zhang 1,  Xue Zhang 1 2,  Ying Liu 2,  Xin Zhou 4,  Peng Shi 4,  Junliang Yuan 5,  Zengqiang Yuan 1 6 7,  Jinbo Cheng 1 3
Affiliations

Affiliations

  • 1 The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China.
  • 2 School of Life Science, Beijing University of Chinese Medicine, Beijing, China.
  • 3 Center on Translational Neuroscience, College of Life & Environmental Science, Minzu University of China, Beijing, China.
  • 4 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • 5 Department of Neurology, Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China.
  • 6 NHC Key Laboratory of Neurodegenerative Diseases, Hengyang Medical School, University of South China, Hengyang, China.
  • 7 Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, Hebei, China.
PMID: 41388745 DOI: 10.1002/glia.70118
Abstract

Exposure to hypoxic environments leads to neurological dysfunction, with recent studies implicating microglia-derived neuroinflammation involved in hypoxia-induced neuronal impairment. However, the underlying pathological mechanisms remain largely unclear. Lipid-droplet-accumulating microglia (LDAM) have been linked to age-related and genetic forms of neurodegeneration, prompting the investigation of their role in hypoxia-induced neuronal impairment. In this study, we observed that hypoxia induced lipid droplets accumulation in microglia, accompanied by increased levels of RETSAT, an enzyme involved in lipid metabolism regulation. Conditional knockout of RETSAT in microglia decreased lipid droplets accumulation and alleviates hypoxia-induced microglial-derived neuroinflammation and oxidative stress, both in vitro and in vivo. Our biological studies indicate that the beneficial effects of RETSAT knockout on lipid droplets degradation are primarily mediated through enhanced activity of hormone-sensitive Lipase (HSL). Furthermore, we found that the hypoxic adaptation-related RETSAT mutation Q247R promotes microglia lipolysis under hypoxic conditions. These findings suggest that RetSat is a potential therapeutic target for the prevention and treatment of hypoxia-induced microglial activation.

Keywords

HSL; RetSat; hypoxia; lipid droplets; microglia activation.

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