Hypothalamic Control of Liver Health and Disease: From Circuits to Pathophysiology and Therapies.

The liver is the body's principal metabolic hub, reprogramming its functions according to physiological demands. Beyond local nutrient and hormonal cues, the hypothalamus acts as a central command node, integrating systemic signals to coordinate hepatic glucose and lipid homeostasis, bile acid flux, and regeneration. Dysregulation of this hypothalamus-liver axis is a core driver of liver disease, from steatotic liver disease to hepatocellular carcinoma. In this Review, we discuss established knowledge and recent advances in the neural and neuroendocrine pathways that connect the hypothalamus to the liver. We examine how specific signals guide physiological adaptation and how their maladaptive plasticity fuels disease progression. We also evaluate emerging therapeutic strategies that target this neuro-hepatic interface, including circuit-specific pharmacology and bioelectronic modulation, and outline key translational challenges. Decoding the hypothalamus-liver axis not only reveals a fundamental principle of inter-organ communication but also points to new approaches for restoring liver homeostasis.