Intercellular communication and multi-organ axis interactions in the pathogenesis of MASLD: a signal-class synthesis graded by disease context and causal status

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition characterised primarily by hepatic steatosis and closely linked to obesity, insulin resistance and type 2 diabetes, and its pathogenesis is now understood as a disorder of communication among hepatocytes, hepatic stellate cells, Kupffer cells and liver sinusoidal endothelial cells, and between the liver and adipose tissue, gut, skeletal muscle, pancreas, heart, kidney, brain and spleen. This review synthesises these axes by organising principle rather than by anatomical list. Crosstalk is classified by signal class, namely lipid flux, cytokines, hepatokines, adipokines, myokines, bile acids, extracellular vesicles, neural circuits and microbial metabolites, and each class is tabulated by source and receiver organs, direction of effect and graded by disease context and causal status. For every axis we distinguish co-occurrence attributable to shared cardiometabolic substrate from experimentally demonstrated organ-to-organ signalling, since only the second supports a mechanistic claim. Three categories of recent work are kept separate, namely new causal evidence, emerging single-cell and spatial concepts and contradictory or qualifying findings; where evidence comes from outside MASLD the provenance is stated, and where a claim is contested the discriminating experiment is specified. Therapeutics are reorganised by regulatory and evidence status rather than by presumed target axis, and one axis not covered systematically by previous reviews, the liver and spleen axis, is set out in full. The framework identifies which mechanistic claims are currently testable in patients and where shared, druggable nodes lie.