{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T09:40:16Z","timestamp":1777887616639,"version":"3.51.4"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Acute pancreatitis (AP) is a severe inflammatory disease where epithelial injury and dysregulated repair are central to pathogenesis, yet the underlying transcriptional mechanisms remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study employed an integrated approach to identify and characterize the transcription factor MXD3 as a master regulator of AP progression. Using single-cell RNA sequencing in a ceruleininduced rat AP model, we delineated a pathogenic epithelial trajectory from ciliated through non-ciliated to a proliferative state, with MXD3 emerging as the most significantly upregulated transcription factor in the proliferative cluster. Subsequent validation in pancreatic ductal epithelial-specific MXD3 knockout rats revealed profound protection against AP, manifesting as reduced histological damage, diminished fibrosis, attenuated neutrophil infiltration (MPO+ cells), and decreased expression of pro-inflammatory cytokines (IL-6, TNF-\u03b1, IL-1\u03b2).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Mechanistically, we demonstrated that MXD3 directly activates the Wnt\/\u03b2-catenin pathway, as evidenced by increased non-phospho \u03b2-catenin, its nuclear accumulation, and transcriptional upregulation of canonical targets (cMyc, Cyclin D1, Axin2). Furthermore, functional rescue experiments confirmed the pathway\u2019s necessity, wherein the \u03b2-catenin inhibitor ICG-001 substantially reversed MXD3-driven apoptosis, necrosis, and pro-inflammatory cytokine secretion (IL-1\u03b2, IL-6, MCP-1)\n                      <jats:italic>in vitro<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings establish a novel MXD3- Wnt\/\u03b2-catenin axis as a crucial mechanism governing epithelial pathology in AP, revealing MXD3 as a promising therapeutic target for this debilitating condition.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphys.2026.1785500","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T04:18:53Z","timestamp":1777609133000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ductal epithelial MXD3 promotes disease progression in acute pancreatitis through Wnt\/\u03b2-catenin-mediated inflammation and injury"],"prefix":"10.3389","volume":"17","author":[{"given":"Xianru","family":"Jia","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Zhoukou Central Hospital Affiliated to Henan Medical University","place":["Zhoukou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingbing","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Zhoukou Central Hospital Affiliated to Henan Medical University","place":["Zhoukou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuejin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Zhoukou Central Hospital Affiliated to Henan Medical University","place":["Zhoukou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1016\/S0140-6736(20)31310-6","article-title":"Acute pancreatitis","volume":"396","author":"Boxhoorn","year":"2020","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"5933","DOI":"10.1038\/s41388-020-01390-0","article-title":"DOCK6 promotes chemo- and radioresistance of gastric cancer by modulating WNT\/\u03b2-catenin signaling and cancer stem cell traits","volume":"39","author":"Chi","year":"2020","journal-title":"Oncogene"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1126\/science.abj0486","article-title":"Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis","volume":"373","author":"Del Poggetto","year":"2021","journal-title":"Science"},{"key":"B4","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1053\/j.gastro.2024.06.008","article-title":"A single-cell atlas of the murine pancreatic ductal tree identifies novel cell populations with potential implications in pancreas regeneration and exocrine pathogenesis","volume":"167","author":"Fern\u00e1ndez","year":"2024","journal-title":"Gastroenterology"},{"key":"B5","doi-asserted-by":"publisher","first-page":"25702","DOI":"10.1038\/s41598-024-76658-6","article-title":"Irisin promotes intestinal epithelial cell proliferation via Wnt\/\u03b2-catenin and focal adhesion kinase signaling pathways","volume":"14","author":"Gaowa","year":"2024","journal-title":"Sci. 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