{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:12:22Z","timestamp":1788415942373,"version":"build-2803163510"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82300738"],"award-info":[{"award-number":["82300738"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004772","name":"Natural Science Foundation of Ningxia Province","doi-asserted-by":"publisher","award":["2024AAC05087"],"award-info":[{"award-number":["2024AAC05087"]}],"id":[{"id":"10.13039\/501100004772","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004179","name":"Ningxia Medical University","doi-asserted-by":"publisher","award":["XT2023039"],"award-info":[{"award-number":["XT2023039"]}],"id":[{"id":"10.13039\/501100004179","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>Akkermansia muciniphila<\/jats:italic>\n                      (AKK) and propionate.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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 \u03b1\u2011SMA. 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\n                      <jats:italic>Akkermansia<\/jats:italic>\n                      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-\u03baB-mediated inflammatory response in the pancreas, and promoted macrophage polarization to the M2 phenotype. Supplementation with\n                      <jats:italic>Akkermansia<\/jats:italic>\n                      or propionate protected against HFD-induced CP through similar signaling pathways, and synergistically activated AMPK signaling while suppressing inflammatory pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1923107","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:14:02Z","timestamp":1788412442000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["SCO\u2011792 alleviates HFD\u2011aggravated chronic pancreatitis by modulating the gut\u2013pancreas axis via the AMPK\/ACC and TLR4\/NF\u2011\u03baB signaling pathways"],"prefix":"10.3389","volume":"17","author":[{"given":"Yanru","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, General Hospital of Ningxia Medical University","place":["Yinchuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningning","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, General Hospital of Ningxia Medical University","place":["Yinchuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijie","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University","place":["Yinchuan, 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