The multiorgan crosstalk network of the liver-brain axis: From molecular mechanisms to emerging therapeutic targets

The liver-brain axis (LBA) represents a sophisticated, dynamic bidirectional communication network that is fundamental to systemic metabolic and homeostatic regulation. This review synthesizes current understanding of the LBA as an integrated, multi-layered system encompassing neural, humoral, immune-inflammatory, metabolic, and circadian signaling pathways. Moving beyond organ-centric perspectives, we detail how hepatic-derived factors-including hepatokines, metabolites, and extracellular vesicles-directly influence cerebral function, while central neural and neuroendocrine outputs dynamically modulate hepatic physiology. Dysregulation within this network underlies a broad spectrum of pathologies, from metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes to neurodegenerative disorders, psychiatric conditions, and hepatocellular carcinoma. We further explore emerging therapeutic strategies aimed at recalibrating this axis, emphasizing innovative approaches such as neuromodulation, chrononutrition, exercise, natural products, and precision gene editing. By adopting a systems-level perspective, this review advocates for a paradigm shift from isolated organ treatment to network-based medicine, highlighting the therapeutic potential of recalibrating inter-organ communication.