Physical activity reshapes intrapancreatic immune and inflammatory programmes to restrain chronic pancreatitis

Background Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder with persistent immune activation and limited therapeutic options. While physical activity (PA) benefits many chronic diseases, it is often presumed neutral or potentially harmful in CP. Objective To assess whether PA protects against CP and defines the underlying mechanisms. Design We analysed the association between PA and CP risk in the UK Biobank cohort (>500 000 participants) and validated findings in an independent clinical cohort. In mice, experimental CP was induced and the effects of exercise interventions on pancreatic injury, fibrosis and immune responses were evaluated via histopathology, immunohistochemistry, flow cytometry, bulk and single-cell RNA-sequencing and proteomics. Results In the UK Biobank, regular PA was independently associated with a lower risk of CP. This association was consistent across alcohol intake strata and disease subtypes. Consistently, physically active patients with CP exhibited milder clinical manifestations. In mice, exercise interventions, including both preconditioning and postdisease initiation, attenuated pancreatic injury, fibrosis and ferroptosis, with resistance exercise providing greater protection. Mechanistically, skeletal muscle-derived extracellular vesicles (EVs) induced by PA accumulated within inflamed pancreata and dampened mitochondrial DNA-driven innate immune activation while promoting inflammation-resolving states, at least in part through modulation of myeloid stimulator of interferon genes (STING) signalling. Importantly, inhibition of EV release partially attenuates these protective effects. Proteomic profiling identified PRDX6 as a muscle-derived vesicular factor that inhibits ferroptosis and, by binding to the zinc-thumb motif of cyclic GMP-AMP synthase, contributes to suppression of STING activation and inflammatory damage. Conclusion PA restrains CP progression by reprogramming pancreatic immune responses and ferroptosis pathways.