Advancing liver metabolic zonation with single-cell and spatial omics

Hepatic carbohydrate and lipid metabolism is strictly regulated by hormones such as insulin, glucagon, cortisol, and adrenaline, dynamically adapting to diet and stress. Metabolic zonation, a key feature of liver function, has been studied for decades. It refers to the spatial arrangement of hepatocytes with distinct metabolic roles along the portal-to-central vein axis, shaped by nutrient and oxygen gradients, as well as signaling molecules. However, traditional methods have struggled to reveal the spatial regulation of gene expression and signaling within these zones. Recent advances in single-cell and spatial omics technologies now allow detailed analysis of gene expression, signaling pathways, and cell-cell interactions with spatial resolution, providing new insights beyond classical models. Metabolic zonation research is rapidly advancing, and the concept of immune zonation, describing the spatial distribution of immune cells, has gained attention for its role in liver metabolism. These findings have improved our understanding of metabolic changes in conditions like fatty liver disease and diabetes. However, many questions remain, including the dynamic effects of diet and hormones and disease-related alterations. This review summarizes past and recent findings on metabolic zonation, explores the role of immune zonation and hormonal regulation, and discusses the latest technologies and future challenges.