The role and mechanisms of the vascular microenvironment in metabolic dysfunction– associated fatty liver disease

Abstract

Metabolic dysfunction–associated fatty liver disease (MAFLD) is the leading cause of chronic liver disease worldwide and is increasingly recognized as a multisystem disorder driven by intertwined metabolic and vascular dysfunction. Beyond the classical features of steatosis, inflammation, and fibrosis, emerging evidence suggests that disruption of the hepatic vascular microenvironment may contribute to MAFLD progression, although its temporal relationship with metabolic injury requires further validation. The liver sinusoid constitutes a highly specialized vascular niche in which liver sinusoidal endothelial cells (LSECs) function as metabolic gatekeepers and mechanosensors, integrating blood flow, shear stress, and nutrient exchange to maintain hepatic homeostasis. In MAFLD, endothelial metabolic reprogramming, reduced nitric oxide bioavailability, and sinusoidal microcirculatory impairment collectively disrupt vascular regulation, thereby promoting lipotoxicity, inflammatory activation, and tissue hypoxia. These processes may be further amplified by multicellular crosstalk, wherein immune cells exacerbate endothelial dysfunction, while hepatic stellate cells (HSCs) promote extracellular matrix deposition, vascular stiffening, and increased sinusoidal resistance. In this review, we synthesize current evidence from a vascular microenvironment perspective and propose a stage-associated conceptual framework encompassing early endothelial stress, immune–endothelial amplification, and fibrotic remodeling. We also discuss emerging therapeutic strategies targeting endothelial metabolism, microcirculatory function, and vascular resistance. By integrating metabolic, inflammatory, and biomechanical processes, this review highlights the hepatic microvasculature as a candidate regulatory hub warranting prospective evaluation as a translational target in MAFLD.