Liver–pancreas communication in disease and drug development

The liver and pancreas are metabolically intertwined organs whose bidirectional communication is critical for maintaining systemic homeostasis. Dysregulation of this inter-organ crosstalk is a central driver in the pathology of a growing list of prevalent diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), liver cancer, acute and chronic pancreatitis, and various forms of diabetes. Given the substantial global health burden of these conditions and the lack of effective, Food and Drug Administration (FDA)-approved pharmacological interventions for those diseases, understanding the intricate mechanisms is an urgent and timely endeavor. This review provides a comprehensive synthesis of recent advancements in deciphering the molecular basis of liver–pancreas communication. We explore the multifaceted signaling networks involved, including the roles of liver-derived hepatokines, pancreas-derived hormones, extracellular vesicles, and metabolic exchanges. This axis is further integrated within broader systemic networks involving the gut, neuronal system, adipose tissue, and skeletal muscle. While clinical trials targeting this communication show promise (e.g., FGF21- and bile acid-related drugs), significant challenges remain, particularly the lack of FDA-approved pharmacological treatments for alcohol-associated liver disease (ALD), and acute/chronic pancreatitis. Future research must elucidate specific signaling pathways, identify novel pancreas-derived factors, and develop innovative therapeutic strategies. In particular, small molecule drug discovery based on polypharmacology, for these complex metabolic and organ-specific diseases.