Liver-brain axis mechanism underlying central immune remodeling triggered by peripheral hepatic damage

Liver dysfunction and various hepatic disorders cause neuropsychiatric abnormalities including depression, anxiety, cognitive impairment and personality changes through liver-brain axis imbalance, greatly worsening patient prognosis. The liver-brain axis acts as a bidirectional network via neural, humoral, immune and gut microbiota pathways, and its disruption dominates liver disease-related central nervous system (CNS) injury. Toxic metabolites such as bilirubin activate the transient receptor potential cation channel subfamily M member 2 (TRPM2)-spleen tyrosine kinase (SYK)-nuclear factor kappa-B (NF-κB) pathway in microglia, triggering excessive glutamatergic synapse phagocytosis in the anterior cingulate cortex (ACC) and sustained neuroinflammation with irreversible neural circuit damage. This review summarizes the pathogenesis of neuropsychiatric complications induced by liver dysfunction and liver transplantation, focusing on blood-brain barrier (BBB) disruption, systemic immune activation, neurotransmitter imbalance and resident immune cell phenotypic shifts. It clarifies four liver-brain axis regulatory pathways, highlights microglial central functions, and addresses gut-liver-brain axis crosstalk, meningeal immunity, choroid plexus barrier damage and circadian rhythm disturbance. It also concludes diagnostic biomarkers including bilirubin and fibroblast growth factor 21 (FGF21), alongside therapeutic targets covering the TRPM2-SYK-NF-κB pathway, microglial polarization and gut microbiota. This study provides a unified theoretical framework for clinical diagnosis, risk stratification and targeted treatment of liver disease-related neuropsychiatric complications, and explains CNS dysfunction mechanisms underlying metabolic dysfunction-associated steatotic liver disease (MASLD), liver cirrhosis and acute-on-chronic liver failure.