Pancreatic-liver crosstalk, novel molecular mediators, and 2025 therapeutic breakthroughs

Obesity, a global public health crisis driven by dysregulated systemic energy homeostasis, is increasingly recognized as a disorder of interorgan communication, with the pancreas and liver serving as central interconnected metabolic hubs. Their bidirectional crosstalk, mediated through neural and humoral pathways, is a key driver of disease progression. Recent breakthroughs have uncovered novel molecular mechanisms amplifying this pathogenic axis: Adipocyte-derived exosomes carrying miR-138-5p directly target pancreatic β-cell SOX4, suppressing insulin secretion and promoting apoptosis, while hepatic RNA demethylase ALKBH5 stabilizes glucagon receptor mRNA and activates lipogenic pathways, exacerbating hyperglycemia and steatosis. Further, colonic inflammation activates hepatic ERK signaling, which is converted into neural signals by the liver and precisely delivered to the pancreas through the liver-pancreas vagus nerve circuit, driving adaptive β-cell proliferation in early obesity by releasing neurotransmitters such as acetylcholine. Traditional pathogenic loops persist: Pancreatic exocrine insufficiency disrupts gut-liver homeostasis, inducing systemic inflammation, and hepatic free fatty acid flux exerts direct and immune-mediated lipotoxicity on pancreatic β-cells, forming a self-perpetuating vicious cycle. Emerging interventions target this axis: GLP-1/GIP dual agonists (e.g., tirzepatide) demonstrate remarkable efficacy in weight loss and non-alcoholic steatohepatitis remission, while time-restricted feeding (e.g., 16:8 regimen) reduces liver fat through circadian and metabolic pathway activation, independent of caloric restriction. This review synthesizes novel interorgan signaling mechanisms and 2025 therapeutic breakthroughs, emphasizing the pancreas-liver axis as a critical target for obesity management.