<scp>RetSat</scp> Knockout Mitigates Hypoxia‐Induced Microglial Activation by Enhancing Lipid Droplets Degradation

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.