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The endocannabinoid system has emerged as a potential modulator of inflammation in AP. We investigated the role of the endocannabinoid 2\u2010arachidonoylglycerol (2\u2010AG) and the cannabinoid receptors CB1 and CB2 during AP. A severity\u2010dependent decrease in circulating 2\u2010AG was found both in patients and a murine AP model. Restoring 2\u2010AG \u2013 by avoiding its degradation via monoacylglycerol lipase inhibitor or direct 2\u2010AG administration \u2013 reduced local and systemic inflammation, modulated peritoneal macrophage polarization, and mitigated lung injury. Notably, endocannabinoid system effects were consistent across sexes. Both cannabinoid receptors were involved in disease pathophysiology. Genetic\n                    <jats:italic>Cnr1<\/jats:italic>\n                    knockout and pharmacological CB2 blockade showed distinct and complementary roles of both receptors in regulating inflammation, immune infiltration, and pulmonary damage. These findings highlight a protective role for 2\u2010AG and highlight the endocannabinoid system \u2013 and cannabinoid receptors in particular \u2013 as a promising therapeutic target to modulate inflammation and reduce systemic complications in acute pancreatitis. \u00a9 2026 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70076","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T08:45:27Z","timestamp":1779180327000},"page":"462-477","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Disrupted endocannabinoid signaling contributes to systemic inflammation in acute pancreatitis"],"prefix":"10.1002","volume":"269","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2106-0307","authenticated-orcid":false,"given":"Paula","family":"Goncalves\u2010Romeu","sequence":"first","affiliation":[{"name":"Respiratory and Immune Repair Group (REPAIR) Germans Trias i Pujol Research Institute (IGTP)  Badalona Spain"},{"name":"Faculty of Biosciences Universitat Autonoma de Barcelona (UAB)  Bellaterra Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"C\u00e1rdenas\u2010Jaen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine Miguel Hernandez University  Elche Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2412-9541","authenticated-orcid":false,"given":"Enrique","family":"de\u2010Madaria","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Dr. Balmis General University Hospital, ISABIAL  Alicante Spain"},{"name":"Centre 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