{"doi":"10.1016/j.ajpath.2023.02.015","title":"SQSTM1/p62 and Hepatic Mallory-Denk Body Formation in Alcohol-Associated Liver Disease","abstract":"Sequestosome 1 (SQSTM1/p62; hereafter p62) is an autophagy receptor protein for selective autophagy primarily due to its direct interaction with the microtubule light chain 3 protein that specifically localizes on autophagosome membranes. As a result, impaired autophagy leads to the accumulation of p62. p62 is also a common component of many human liver disease–related cellular inclusion bodies, such as Mallory-Denk bodies, intracytoplasmic hyaline bodies, α1-antitrypsin aggregates, as well as p62 bodies and condensates. p62 also acts as an intracellular signaling hub, and it involves multiple signaling pathways, including nuclear factor erythroid 2–related factor 2, NF-κB, and the mechanistic target of rapamycin, which are critical for oxidative stress, inflammation, cell survival, metabolism, and liver tumorigenesis. This review discusses the recent insights of p62 in protein quality control, including the role of p62 in the formation and degradation of p62 stress granules and protein aggregates as well as regulation of multiple signaling pathways in the pathogenesis of alcohol-associated liver disease. Sequestosome 1 (SQSTM1/p62; hereafter p62) is an autophagy receptor protein for selective autophagy primarily due to its direct interaction with the microtubule light chain 3 protein that specifically localizes on autophagosome membranes. As a result, impaired autophagy leads to the accumulation of p62. p62 is also a common component of many human liver disease–related cellular inclusion bodies, such as Mallory-Denk bodies, intracytoplasmic hyaline bodies, α1-antitrypsin aggregates, as well as p62 bodies and condensates. p62 also acts as an intracellular signaling hub, and it involves multiple signaling pathways, including nuclear factor erythroid 2–related factor 2, NF-κB, and the mechanistic target of rapamycin, which are critical for oxidative stress, inflammation, cell survival, metabolism, and liver tumorigenesis. This review discusses the recent insights of p62 in protein quality control, including the role of p62 in the formation and degradation of p62 stress granules and protein aggregates as well as regulation of multiple signaling pathways in the pathogenesis of alcohol-associated liver disease. Long-term alcohol consumption can lead to alcohol-associated liver disease (ALD), which is the leading cause of cirrhosis-related deaths.1Paik J.M. Golabi P. Younossi Y. Mishra A. Younossi Z.M. Changes in the global burden of chronic liver diseases from 2012 to 2017: the growing impact of NAFLD.Hepatology. 2020; 72: 1605-1616Google Scholar In line with the Global Status Report on Alcohol and Health in 2018 from World Health Organization, alcohol-attributable liver cirrhosis caused >600,000 deaths.2World Health OrganizationGlobal status report on alcohol and health 2018. World Health Organization, 2019Google Scholar The pathogenesis of ALD includes alcoholic fatty liver, alcoholic hepatitis (AH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).2World Health OrganizationGlobal status report on alcohol and health 2018. World Health Organization, 2019Google Scholar, 3Bruha R. Dvorak K. Petrtyl J. Alcoholic liver disease.World J Hepatol. 2012; 4: 81Google Scholar, 4Qian H. Chao X. Williams J. Fulte S. Li T. Yang L. Ding W.-X. Autophagy in liver diseases: a review.Mol Aspects Med. 2021; 82: 100973Google Scholar According to the spectrum studies of ALD, approximately 90% to 100% heavy alcohol drinkers develop fatty liver, which is manifested as increased accumulation of lipid droplets (LDs) in hepatocytes. Nearly one of four drinkers with fatty liver develop AH, which is characterized by increased hepatocyte death and hepatic inflammation. Up to one of five patients with AH advanced to cirrhosis, with the liver becoming irreversibly scarred, and finally a few heavy drinkers can even develop HCC.5European Association for the Study of LiverEASL clinical practical guidelines: management of alcoholic liver disease.J Hepatol. 20","journal":"American Journal Of Pathology","year":2023,"id":335151,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9473,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":284312,"name":"Wen‐Xing Ding","orcid":"0000-0002-3167-5073","position":1,"is_corresponding":false},{"id":288631,"name":"Hui Qian","orcid":"0000-0001-9571-5815","position":0,"is_corresponding":true}],"reference_count":159,"raw_metadata":null,"created_at":"2026-07-19T01:09:58.338267Z","pmid":"36906265","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}