{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:02:46Z","timestamp":1784264566788,"version":"3.55.0"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Crohn\n                      <jats:bold>\u2019<\/jats:bold>\n                      s disease (CD) is characterized by persistent intestinal inflammation, immune dysregulation, and intestinal barrier dysfunction. Inflammasome-mediated pyroptosis is an innate immune mechanism increasingly implicated in inflammatory bowel disease (IBD); however, the upstream molecular signals associated with NLRP3\u2013Caspase-1\u2013GSDMD activation in CD remain insufficiently defined. Here, we explored whether the angiopoietin-1 (ANGPT1)\u2013gamma-aminobutyric acid receptor-associated protein (GABARAP) axis is associated with CD-related pyroptotic signaling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Protein quantitative trait locus (pQTL)-based two-sample Mendelian randomization (MR) was performed to prioritize pyroptosis-related proteins genetically associated with CD risk. Putative upstream regulators of GABARAP were then examined by two-step MR and mediation analysis. Functional validation was performed using a dextran sulfate sodium (DSS)-induced murine colitis model and LPS plus nigericin-induced cell models of NLRP3 inflammasome activation. ANGPT1\u2013GABARAP signaling and the NLRP3\u2013Caspase-1\u2013GSDMD pathway were evaluated following GABARAP or ANGPT1 knockdown and exogenous recombinant human ANGPT1 (rhANGPT1) supplementation, by qRT-PCR, western blotting, ELISA, and LDH release assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MR analysis prioritized GABARAP as a suggestive protective candidate for CD, with genetically predicted higher GABARAP levels associated with a decreased disease risk (OR\u00a0=\u00a00.563, 95% CI 0.327\u20130.968, P\u00a0=\u00a00.038). Two-step MR further suggested a putative genetic association between ANGPT1 and GABARAP, and mediation analysis indicated that GABARAP may partially mediate the genetically predicted ANGPT1\u2013CD association, with an estimated mediation proportion of 22.97%. DSS-induced colitis was associated with reduced ANGPT1 and GABARAP expression, along with increased NLRP3 expression, Caspase-1 processing, GSDMD-N accumulation, and elevated IL-1\u03b2, IL-18, and LDH levels.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , silencing either GABARAP or ANGPT1 enhanced NLRP3 inflammasome-associated pyroptotic signaling under LPS plus nigericin stimulation, whereas rhANGPT1 treatment partially attenuated these responses in association with restored GABARAP expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings support a potential role for the ANGPT1\u2013GABARAP axis in NLRP3 inflammasome-mediated pyroptosis associated with intestinal inflammation. Together, these results provide a genetically informed framework for understanding pyroptosis-related inflammatory signaling in CD and support further investigation of the potential therapeutic relevance of this axis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1867825","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T04:29:15Z","timestamp":1781065755000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["ANGPT1\u2013GABARAP axis modulates NLRP3 inflammasome\u2013mediated pyroptosis in Crohn\u2019s disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Yanchen","family":"Li","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyan","family":"He","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyang","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahui","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Diseases","place":["Shijiazhuang, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2026.1239","article-title":"Management of crohn disease in adults","volume":"335","author":"Choden","year":"2026","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2025.08.032","article-title":"Comparative efficacy of advanced therapies for management of moderate-to-severe crohn\u2019s disease: 2025 AGA evidence synthesis","volume":"169","author":"Singh","year":"2025","journal-title":"Gastroenterology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-042624-121548","article-title":"Gasdermins, executors of pyroptosis: a decade in perspective","volume":"21","author":"Zhou","year":"2026","journal-title":"Annu Rev 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