SCO‑792 alleviates HFD‑aggravated chronic pancreatitis by modulating the gut–pancreas axis via the AMPK/ACC and TLR4/NF‑κB signaling pathways

Background Chronic pancreatitis (CP) is an inflammatory disorder that manifests as pancreatic fibrosis and exocrine insufficiency, and premature activation of trypsinogen to trypsin. Enteropeptidase has emerged as a promising therapeutic target in CP due to its critical role in activating trypsinogen. The aim of this study was to assess the effects of SCO-792, a novel enteropeptidase inhibitor, on high-fat diet (HFD)-aggravated CP, and explore the underlying mechanisms. Methods A mouse model of HFD-aggravated CP was established by chronic caerulein administration. The protective effects of SCO-792 were evaluated through histological analysis, biochemical assays, and molecular techniques. The composition of the gut microbiota was analyzed by 16S rRNA gene sequencing, and the fecal levels of short-chain fatty acids (SCFAs) were measured. The involvement of the gut-pancreas axis was further validated by supplementation with Akkermansia muciniphila (AKK) and propionate. Results SCO-792 treatment significantly alleviated HFD-aggravated pancreatic injury and fibrosis, as indicated by reduced histological scores, decreased collagen deposition, and downregulated protein levels of collagen I and α‑SMA. At the metabolic level, SCO-792 regulated pancreatic lipid metabolism homeostasis via the AMPK/ACC pathway. SCO-792 also restored the gut microbiota by increasing the abundance of Akkermansia and other beneficial bacteria, and enhancing production of SCFAs. Furthermore, SCO-792 significantly reduced the translocation of serum lipopolysaccharide(LPS) by maintaining intestinal barrier integrity. The decrease in systemic endotoxin levels eventually blocked the TLR4/NF-κB-mediated inflammatory response in the pancreas, and promoted macrophage polarization to the M2 phenotype. Supplementation with Akkermansia or propionate protected against HFD-induced CP through similar signaling pathways, and synergistically activated AMPK signaling while suppressing inflammatory pathways. Conclusion SCO-792 mitigated HFD-aggravated pancreatitis in mice by modulating the gut-pancreas axis, indicating its potential as a preventive and therapeutic agent for metabolic pancreatic diseases.