{"doi":"10.1016/j.ajpath.2023.03.009","title":"The Dynamic Role of Endoplasmic Reticulum Stress in Chronic Liver Disease","abstract":"Chronic liver disease (CLD) is a major worldwide public health threat, with an estimated prevalence of 1.5 billion individuals with CLD in 2020. Chronic activation of endoplasmic reticulum (ER) stress–related pathways is recognized as substantially contributing to the pathologic progression of CLD. The ER is an intracellular organelle that folds proteins into their correct three-dimensional shapes. ER-associated enzymes and chaperone proteins highly regulate this process. Perturbations in protein folding lead to misfolded or unfolded protein accumulation in the ER lumen, resulting in ER stress and concomitant activation of the unfolded protein response (UPR). The adaptive UPR is a set of signal transduction pathways evolved in mammalian cells that attempts to reestablish ER protein homeostasis by reducing protein load and increasing ER-associated degradation. However, maladaptive UPR responses in CLD occur due to prolonged UPR activation, leading to concomitant inflammation and cell death. This review assesses the current understanding of the cellular and molecular mechanisms that regulate ER stress and the UPR in the progression of various liver diseases and the potential pharmacologic and biological interventions that target the UPR. Chronic liver disease (CLD) is a major worldwide public health threat, with an estimated prevalence of 1.5 billion individuals with CLD in 2020. Chronic activation of endoplasmic reticulum (ER) stress–related pathways is recognized as substantially contributing to the pathologic progression of CLD. The ER is an intracellular organelle that folds proteins into their correct three-dimensional shapes. ER-associated enzymes and chaperone proteins highly regulate this process. Perturbations in protein folding lead to misfolded or unfolded protein accumulation in the ER lumen, resulting in ER stress and concomitant activation of the unfolded protein response (UPR). The adaptive UPR is a set of signal transduction pathways evolved in mammalian cells that attempts to reestablish ER protein homeostasis by reducing protein load and increasing ER-associated degradation. However, maladaptive UPR responses in CLD occur due to prolonged UPR activation, leading to concomitant inflammation and cell death. This review assesses the current understanding of the cellular and molecular mechanisms that regulate ER stress and the UPR in the progression of various liver diseases and the potential pharmacologic and biological interventions that target the UPR. Chronic liver disease (CLD) affects 1.5 billion individuals worldwide and can lead to complications such as cirrhosis and liver cancers.1Moon A.M. Singal A.G. Tapper E.B. Contemporary epidemiology of chronic liver disease and cirrhosis.Clin Gastroenterol Hepatol. 2020; 18: 2650-2666Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar,2Cheemerla S. Balakrishnan M. Global epidemiology of chronic liver disease.Clin Liver Dis (Hoboken). 2021; 17: 365-370Crossref PubMed Scopus (122) Google Scholar Endoplasmic reticulum (ER) stress is a major contributing factor to the pathogenesis of many CLDs, including hepatic biliary diseases, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma (HCC).3Liu X. Green R.M. Endoplasmic reticulum stress and liver diseases.Liver Res. 2019; 3: 55-64Crossref PubMed Scopus (71) Google Scholar The ER is responsible for several vital intracellular functions, including calcium homeostasis and steroid hormone and lipid biosynthesis.4Wang M. Kaufman R.J. Protein misfolding in the endoplasmic reticulum as a conduit to human disease.Nature. 2016; 529: 326-335Crossref PubMed Scopus (953) Google Scholar Importantly, the ER is also a key player in the synthesis, folding, trafficking, and degradation of at least one-third of all eukaryotic proteins. Disruption of ER homeostasis creates a unique cellular state termed ER stress. Several physiological or pathological stimuli are identified as","journal":"American Journal Of Pathology","year":2023,"id":328878,"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":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9576,"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":772554,"name":"Grayson W. Way","orcid":"0000-0002-5765-2064","position":1,"is_corresponding":false},{"id":904095,"name":"Jing Zeng","orcid":"0000-0001-7764-155X","position":2,"is_corresponding":false},{"id":1050882,"name":"Marissa K. Lipp","orcid":"0009-0005-5349-5283","position":3,"is_corresponding":false},{"id":268726,"name":"Huiping Zhou","orcid":"0000-0002-0050-372X","position":4,"is_corresponding":false},{"id":723025,"name":"Kaitlyn G. Jackson","orcid":"0000-0003-2663-9593","position":0,"is_corresponding":true}],"reference_count":102,"raw_metadata":null,"created_at":"2026-07-19T01:08:56.940647Z","pmid":"37028592","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":[]}