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

Figure 1 The mechanism diagram delineates the core pathways by which pathological crosstalk between the pancreas and liver drives metabolic dysfunction in the context of obesity. Adipose tissue-derived exosomes carrying miR-138-5p inhibit insulin secretion and promote apoptosis in pancreatic β-cells. Concurrently, mediators such as lipopolysaccharide from intestinal inflammation reach the liver via the portal vein, polarizing Kupffer cells toward a pro-inflammatory M1 phenotype and triggering hepatic inflammation. Functioning as a metabolic hub, the liver exhibits upregulated expression of the RNA demethylase ALKBH5. This enzyme exacerbates hyperglycemia by stabilizing glucagon receptor mRNA and promotes de novo lipogenesis by activating the EGFR-mTORC1 pathway. These processes are reinforced by a vicious cycle mediated by “free fatty acid (FFA) flux”: Insulin resistance leads to increased lipolysis and FFA influx into the liver, aggravating hepatic lipid deposition and inflammation. The stressed liver, in turn, releases inflammatory signaling molecules including small extracellular vesicles and fetuin-A, which further impair pancreatic β-cell function, resulting in insufficient insulin secretion, thereby creating a closed loop that amplifies metabolic dysregulation. Emerging therapies directly target this axis: GLP-1/GIP dual receptor agonists (e.g., Tirzepatide) coordinately act on the pancreas, liver, and central nervous system to promote insulin secretion and alleviate hepatic steatosis and inflammation. Complementarily, the 16:8 time-restricted feeding regimen exerts therapeutic effects by activating key hepatic metabolic pathways (e.g., AMPK/PGC-1α/PPARα) to enhance lipid oxidation and by remodeling the gut microbiota to improve circadian metabolic rhythm. FFA: Free fatty acid; GCGR: Glucagon receptor; EGFR: Epidermal growth factor receptor.