{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T20:06:29Z","timestamp":1793995589697,"version":"4.8.0"},"reference-count":55,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"unspecified","delay-in-days":11,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R01AA031230"],"award-info":[{"award-number":["R01AA031230"]}]},{"name":"National Institute of Health","award":["R21 AA030617"],"award-info":[{"award-number":["R21 AA030617"]}]},{"name":"National Institute of Health","award":["R37 AA020518"],"award-info":[{"award-number":["R37 AA020518"]}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["R24AA025017"],"award-info":[{"award-number":["R24AA025017"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["egastro"],"accepted":{"date-parts":[[2025,10,21]]},"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Alcohol-associated liver disease (ALD) is a global health problem without an effective treatment. Mallory-Denk body (MDB) is a protein aggregate commonly found in alcohol-associated hepatitis (AH). MDB primarily contains ubiquitinated proteins, cytokeratin 8 and sequestosome 1 (SQSTM1)\/p62. Stress granule (SG) is a cytosolic, membrane-less aggregate composed of various RNA-binding proteins and untranslated mRNA. However, the role and mechanisms of MDB and SG induced by alcohol and their implications in the pathogenesis of ALD remain largely unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>SQSTM1\/p62 whole body knockout and matched wild-type mice were subjected to the Gao-binge alcohol model or fed a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet alongside Gao-binge alcohol model. ALD mouse liver tissues and human AH liver tissues underwent immunohistochemistry (IHC) staining and western blot analysis for SG and MDB markers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We found that the livers of patients with AH had higher levels of SQSTM1\/p62 (MDB marker) and Ras-GTPase-activating protein-binding protein 1 (an SG marker) using IHC staining, and these increased protein levels were enriched in detergent-insoluble fractions compared with healthy individuals. We further discovered that Gao-binge alcohol feeding increased insoluble SG markers, such as phosphorylated eukaryotic initiation factor 2 in mouse livers. Mice fed a DDC diet with Gao-binge alcohol had greater hepatic MDB formation and liver injury than those fed either diet alone. Loss of SQSTM1\/p62 led to reduced protein aggregation involved in SGs and MDBs but increased liver injury in DDC plus Gao-binge alcohol-fed mice, indicating that SQSTM1\/p62 is required for MDB formation and protects against alcohol-induced liver injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Chronic plus binge alcohol exposure increases hepatic MDBs and moderate levels of SGs. p62\/SQSTM1 is critical for the formation but is not essential for the clearance of MDBs, a process that may act as an adaptive protective mechanism against ALD.<\/jats:p>\n                  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