Spatial immune dysregulation in MASLD: integration of lobular zoning, metabolism and immune function

Most prior studies on immune-related fatty liver disease have focused on changes in immune cell quantity and composition. However, this "cell-count model" does not fully explain the regional onset of fibrosis, spatial heterogeneity of lesions, or variable immunotherapy responses. Immune dysregulation in metabolic dysfunction-associated steatotic liver disease (MASLD) involves not only compositional changes but also spatial redistribution and functional alterations of immune cells within specific hepatic lobule regions. Emerging multi-omics and spatial transcriptomic data suggest that chemokine gradient remodeling, metabolic microenvironment reprogramming, and circadian rhythm disruption may drive immune cell relocation along the portal-central axis. We propose that immune dysregulation in MASLD reflects a disruption of spatial immune homeostasis and introduce the liver lobule as the basic unit for spatial immune analysis. The lobule comprises three functionally distinct zones: the periportal zone (zone 1), which serves as the primary immune surveillance barrier; the pericentral zone (zone 3), characterized by metabolic stress and functional impairment; and the fibrotic septum, which in advanced disease creates a structurally confined immunosuppressive niche. To quantify regional T cell dysfunction, we propose a Regional Exhaustion Index (REI) as a conceptual framework, calculated as the ratio of PD-1⁺TIM-3⁺ CD8⁺ T cells to total CD8⁺ T cells within a defined microanatomical region. This metric translates regional immune conditions into a quantifiable measure of T cell functional impairment across different lobular zones. We outline how chemokine remodeling, metabolic reprogramming, and circadian disruption drive spatially distinct immune alterations: reduced immune surveillance in zone 1, functional impairment in zone 3, and structural confinement in the fibrotic septum. We also discuss the translational potential of this framework for biomarker discovery, patient stratification, and targeted therapy. The REI remains an exploratory metric requiring validation of its biological meaning and clinical utility. Current evidence is largely correlational, and the causal role of spatial immune changes in disease progression demands further investigation. Nonetheless, this spatial perspective complements existing paradigms and may guide the development of spatially targeted therapeutic strategies.