MASLD: Spatial Mechanisms and New Therapeutics.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of liver injury ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), a progressive inflammatory state associated with hepatocyte injury, fibrosis, cirrhosis, and hepatocellular carcinoma. Increasing evidence suggests that progression to MASH is not spatially uniform across the liver. Instead, it reflects region-specific metabolic stress, inflammatory signaling, and fibrogenic remodeling along the porto-central axis of the hepatic lobule. Recent advances in spatial transcriptomics, lipidomics, proteomics, and multiplex imaging have provided new insight into how hepatocytes, immune cells, endothelial cells, and hepatic stellate cells interact within distinct hepatic microenvironments during disease progression. In this review, we discuss emerging concepts linking hepatic zonation to steatosis, inflammation, fibrosis, and extracellular matrix remodeling in MASLD and MASH. We highlight how disruption of normal lobular organization contributes to a progressive loss of metabolic compartmentalization and to the amplification of inflammatory and fibrogenic signaling. We additionally examine how spatial disease programs differ between adult and pediatric MASLD, particularly given the periportal-predominant injury patterns frequently observed in children and the current lack of pediatric-focused mechanistic studies. Finally, we discuss recently approved therapies and emerging therapeutic strategies within the context of hepatic microenvironment remodeling and disease heterogeneity. Collectively, these findings support a framework in which MASLD and MASH are spatially organized diseases driven by dynamic multicellular interactions, emphasizing the importance of incorporating zonation and tissue context into future mechanistic studies and therapeutic development.