Liver sinusoidal endothelial cell fenestrations in metabolic liver disease: from molecular mechanisms to therapeutic perspectives

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), constitute major causes of hepatic morbidity worldwide. Central to the pathophysiology of these conditions is the progressive impairment of liver sinusoidal endothelial cells (LSECs), whose characteristic fenestrated architecture is indispensable for hepatic homeostasis. Capillarization, defined as the loss of LSEC fenestrations, propels disease progression by disrupting the equilibrium between pro-fenestration and pro-capillarization signaling cascades. This review critically appraises the LSEC Fenestration Signaling Nexus as a central, targetable mechanism in metabolic liver disease and assesses emerging therapeutic strategies engineered to restore fenestrations. We present a translational roadmap that prioritizes combinatorial pharmacological approaches and LSEC-specific biomarkers for precision medicine. This integrative framework furnishes new perspectives for rational drug development and individualized therapeutic strategies in metabolic liver disease.