Role of central and peripheral serotonin in liver physiology and diseases

Steatotic liver diseases (SLD) associated with metabolic dysfunction (Metabolic dysfunction-Associated Steatotic Liver Disease: MASLD), chronic alcohol consumption (alcohol-associated liver disease: ALD), or both (MetALD) represent a major health issue worldwide. These chronic liver diseases are major drivers of fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and liver-related mortality, with limited treatments currently available. Their progression is fueled by persistent disruptions in hepatic metabolism, inflammation, and tissue remodeling. The autonomic nervous system, notably its regulatory role in hepatic function, is receiving increasing attention as a key mediator of pathogenesis of liver disease. Serotonin (5-hydroxytryptamine, 5-HT) has emerged as a pivotal regulator of all these processes. Acting via combined central and peripheral pathways and a range of receptor subtypes, 5-HT modulates hepatic glucose and lipid metabolism, immune responses, fibrogenesis, and liver regenerative capacity. In this review, we explore the multifaceted role of 5-HT signaling in metabolic control, obesity, liver physiology, and chronic liver diseases. Our focus extends beyond the direct effects of 5-HT on liver cell populations to its interaction with the autonomic nervous system, metabolic hormones, and the gut-liver-brain axis. Lastly, we discuss how 5-HT's dual origin and pleiotropic effects may offer therapeutic avenues for MASLD, ALD, and HCC.