The hepatic sinusoid as a regulatory niche: From cellular specialization to precision hepatology

The hepatic sinusoid is increasingly recognized as a multicellular, spatially organized and therapeutically actionable regulatory niche rather than merely a specialized microvascular bed. Liver sinusoidal endothelial cells, hepatic stellate cells, Kupffer cells, recruited leukocytes, lymphocytes, cholangiocytes, hepatocytes and extracellular matrix components form dynamic networks that coordinate vascular exchange, immune surveillance, metabolic zonation, tissue repair and systemic communication. Recent advances in single-cell and spatial omics, quantitative imaging, mechanobiology and human tissue models have revealed how endothelial dedifferentiation, macrophage and T-cell programming, stellate cell plasticity, extracellular matrix remodeling and stromal control of cancer immunity interact across disease stages. These insights recast fibrosis, portal hypertension, metabolic dysfunction-associated steatotic liver disease and liver cancer as disorders of sinusoidal communication and niche organization, while linking sinusoidal dysfunction to aging and extrahepatic axes. In this review, we trace the evolution of sinusoidal research from cellular specialization to integrated niche biology, focusing on the next unresolved layer: which cell-cell interactions are causal, how they change with disease stage and how they can be measured or perturbed in human tissue. We define priorities for mapping disease-stage-specific human niches, restoring protective functions, developing composite biomarkers and standardizing translational platforms. The hepatic sinusoid is considered here as a tissue-level regulatory unit whose failure can be interrogated through coupled vascular, stromal, immune, metabolic and mechanical readouts.