Oxysterol Signaling Within the Microbiome‐Regulated Gut–Liver–Brain Axis: Implications for Metabolic Homeostasis and Neurodegeneration

The gut-liver-brain axis integrates metabolic and inflammatory signals that influence systemic homeostasis and cognitive function. While current models emphasize short-chain fatty acids and bile acids, they do not fully explain lipid-driven neurodegenerative processes. Oxysterols, oxidized derivatives of cholesterol, are emerging as key signaling molecules that bridge peripheral metabolism and brain function. Generated at the gut-liver interface through enzymatic and oxidative pathways, oxysterols regulate lipid and glucose metabolism via nuclear receptors, including liver X receptors and farnesoid X receptor. Importantly, specific oxysterols cross the blood brain barrier, enabling bidirectional communication between the periphery and central nervous system. By modulating neuroinflammation and synaptic function, oxysterols provide a mechanistic link between metabolic dysfunction and cognitive decline.