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Severe acute pancreatitis (SAP) has high morbidity and mortality, affecting the liver, kidneys, and lungs. Autophagy maintains pancreatic homeostasis, with VMP1-mediated selective autophagy (zymophagy) preventing intracellular zymogen activation and acinar cell death. This study examines the protective role of VMP1 (Vacuole Membrane Protein 1)-induced autophagy using ElaI-VMP1 transgenic mice in a necrohemorrhagic SAP model (Hartwig\u2019s model). ElaI-VMP1 mice show significantly reduced pancreatic injury, including lower necrosis, edema, and inflammation, compared to wild-type (WT) mice. Biochemical markers (lactate dehydrogenase-LDH-, amylase, and lipase) and histopathology confirm that VMP1 expression mitigates pancreatic damage. Increased zymophagy negatively correlates with acinar necrosis, reinforcing its protective role. Beyond the pancreas, ElaI-VMP1 mice exhibit preserved liver, kidney, and lung histology, indicating reduced systemic organ damage. The liver maintains normal architecture, kidneys show minimal tubular necrosis, and lung inflammation features are reduced compared to WT mice. Our results confirm that zymophagy functions as a protective pathophysiological mechanism against pancreatic and extrapancreatic tissue injury in SAP. Further studies on the mechanism of VMP1-mediated selective autophagy in AP are necessary to determine its relevance and possible modulation to prevent the severity of AP.<\/jats:p>","DOI":"10.3390\/ijms26073196","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T03:25:02Z","timestamp":1743391502000},"page":"3196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["VMP1 Constitutive Expression in Mice Dampens Pancreatic and Systemic Histopathological Damage in an Experimental Model of Severe Acute Pancreatitis"],"prefix":"10.3390","volume":"26","author":[{"given":"Veronica","family":"Boggio","sequence":"first","affiliation":[{"name":"Instituto de Bioqu\u00edmica y Biolog\u00eda Molecular Prof. Alberto Boveris, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Universidad de Buenos Aires, Buenos Aires 1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3772-8850","authenticated-orcid":false,"given":"Claudio Daniel","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Centro de Educaci\u00f3n Medica e Investigaciones Cl\u00ednicas (CEMIC), Hospital Universitario Saavedra, Buenos Aires 1431, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsa","family":"Zotta","sequence":"additional","affiliation":[{"name":"Instituto de Bioqu\u00edmica y Biolog\u00eda Molecular Prof. Alberto Boveris, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Universidad de Buenos Aires, Buenos Aires 1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4321-196X","authenticated-orcid":false,"given":"Alejandro","family":"Ropolo","sequence":"additional","affiliation":[{"name":"Instituto de Bioqu\u00edmica y Biolog\u00eda Molecular Prof. Alberto Boveris, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Universidad de Buenos Aires, Buenos Aires 1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2456-747X","authenticated-orcid":false,"given":"Maria Ines","family":"Vaccaro","sequence":"additional","affiliation":[{"name":"Instituto de Bioqu\u00edmica y Biolog\u00eda Molecular Prof. Alberto Boveris, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Universidad de Buenos Aires, Buenos Aires 1113, Argentina"},{"name":"Centro de Educaci\u00f3n Medica e Investigaciones Cl\u00ednicas (CEMIC), Hospital Universitario Saavedra, Buenos Aires 1431, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1053\/j.gastro.2018.11.082","article-title":"Acute Pancreatitis: A Multifaceted Set of Organelle and Cellular Interactions","volume":"156","author":"Habtezion","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/s41575-019-0158-2","article-title":"New insights into acute pancreatitis","volume":"16","author":"Lee","year":"2019","journal-title":"Nat. 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