Liver endothelial zonation orchestrates hepatic steatosis onset through retinoic acid-regulated FGF1.

The contribution of liver sinusoidal endothelial cell (LSEC) zonation to metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis remains undefined. We identified selective lipid deposition in the pericentral zone during early MASLD. Multiomics analyses confirmed enhanced pericentral lipid metabolism in both hepatocytes and LSECs. Mechanistically, pericentral LSEC marker c-Kit transcriptionally activated FGF1 via nuclear receptor RXRG, which suppressed hepatocellular lipid accumulation through FGFR4 signaling. Retinoic acid (RXRG's endogenous ligand and active vitamin A metabolite) phenocopied FGF1's antisteatotic effects. Clinical data revealed an inverse correlation between dietary vitamin A and MASLD severity, suggesting therapeutic potential of vitamin A supplementation for early intervention.