{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T20:06:34Z","timestamp":1793995594311,"version":"4.8.0"},"reference-count":36,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T00:00:00Z","timestamp":1742601600000},"content-version":"unspecified","delay-in-days":80,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 AA011576"],"award-info":[{"award-number":["R01 AA011576"]}]},{"name":"NIH","award":["R01 AA017729"],"award-info":[{"award-number":["R01 AA017729"]}]},{"name":"NIH","award":["R01 AG072899"],"award-info":[{"award-number":["R01 AG072899"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["egastro"],"accepted":{"date-parts":[[2025,2,27]]},"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Gasdermin D (GSDM-D), a key executor of pyroptosis, is increased in various liver diseases and contributes to disease progression. Alcohol induces inflammasome activation and cell death, which are both linked to GSDM-D activation. However, its role in alcohol-induced acute-on-chronic liver failure (ACLF) remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>ACLF was induced in GSDM-D-deficient or wild-type (WT) mice by 28-day bile duct ligation surgery plus a single 5\u2009g\/kg alcohol binge leading to acute decompensation. Nine hours after the alcohol binge, blood, liver, kidney and cerebellum specimens were collected for analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Active GSDM-D was significantly increased in humans and mice ACLF livers compared with both healthy controls and cirrhotic livers. GSDM-D-deficient mice with ACLF showed decreased inflammation, neutrophil infiltration and fibrosis in the liver, together with a reduction in pyroptotic, apoptotic and necroptotic death, compared with WT ACLF mice. Notably, GSDM-D-deficient mice also showed decreased liver regeneration and hepatocyte function. This was associated with an increase in senescence and expression of stem-like\/cholangiocyte markers in the liver. Interestingly, in the kidney, GSDM-D-deficient mice showed an increase in histopathological damage score, decreased function and increased expression of necroptosis-related genes. In the cerebellum, GSDM-D deficiency increased the expression of neuroinflammation markers, astrocyte activation and apoptosis-related genes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our data indicate that GSDM-D deficiency has organ-specific effects in ACLF. While it reduces inflammation, neutrophil activation, cell death and fibrosis in the liver, GSDM-D deficiency impairs the synthetic function and increases senescence in hepatocytes. GSDM-D deficiency also increases kidney injury and neuroinflammation in ACLF.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/egastro-2024-100151","type":"journal-article","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T01:35:41Z","timestamp":1742693741000},"page":"e100151","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Gasdermin D deletion prevents liver injury and exacerbates extrahepatic damage in a murine model of alcohol-induced ACLF"],"prefix":"10.1136","volume":"3","author":[{"given":"Mart\u00ed","family":"Ortega-Ribera","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashanth Thevkar","family":"Nagesh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditi","family":"Datta","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0836-2527","authenticated-orcid":false,"given":"Gyongyi","family":"Szabo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Broad Institute, Cambridge, Massachusetts, 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