Vagal nerve innervation divergence in liver/pancreas: A forgotten key to endocrine recovery after transplantation?

As the cross talk of the parasympathetic nervous system, the vagus nerve exerts organ-specific regulatory effects on hepatic and pancreatic endocrine homeostasis, yet its divergent innervation patterns and their implications for post-transplant functional recovery remain understudied. This review summarizes the anatomical and functional differences of the vagus nerve in the liver and pancreas, and discusses how surgical denervation and incomplete re-innervation affect endocrine recovery after liver and pancreatic transplantation. At the anatomical level, vagus nerve fibers in the liver are relatively sparse and travel along the portal tripa, mainly terminating in the perihilar blood vessels and biliary tract ecological loci, with limited direct parenchymal synapses. This structure is conducive to metabolic perception and indirect regulation of liver glucose flux, bile acid-dependent signaling, and inflammatory tension. In contrast, pancreatic vagus nerve input enters through periarterial/periductal channels and is relays through pancreatic ganglia, forming dense cholinergic efferent control over pancreatic islet α/β/δ cells, supporting rapid and precise insulin-glucagon coordination and counterregulation responses. Clinically, recent preclinical trials and translational studies demonstrate that vagal nerve integrity-often compromised during transplant surgery-serves as a pivotal prognostic marker for endocrine recovery: Preserved vagal innervation is associated with accelerated glucose metabolism normalization and reduced post-transplant complications (e.g., insulin resistance, graft rejection). Notably, frontier strategies such as intraoperative vagal nerve-sparing techniques, targeted neuromodulation (e.g., vagus nerve stimulation), and stem cell-derived neurotrophic factor delivery have shown promising potential in mitigating denervation-induced endocrine dysfunction. This review emphasizes that deciphering the organ-specific vagal innervation mechanisms holds great promise for optimizing precision transplant surgery and developing novel neuromodulatory therapies, which may revolutionize the prognosis of liver and pancreatic transplant recipients.