{"doi":"10.1016/j.jcmgh.2022.04.010","title":"Linking of Senescence to Autophagy Deficiency in Chronic Liver Disease","abstract":"Cellular senescence is a state of irreversible cell-cycle arrest while cells still maintain metabolic activity. Senescence generally is activated as an adaptive response to stresses, such as oxidative stress, oncogene activation, and DNA damage. Morphologically, senescent cells have an enlarged size and flattened morphology with nuclear accumulation of senescence-associated heterochromatic foci and senescence-associated DNA damage foci. Although there are no universal biomarkers for senescence, senescent cells generally have increased β-galactosidase activity; increased cell-cycle inhibitory proteins; such as p21/CDKN1A, p16/CDKN2A, and TP53; as well as increased secretion of a variety of factors, collectively termed as senescence-associated secretory phenotype (SASP).1Aravinthan A.D. Alexander G.J.M. Senescence in chronic liver disease: Is the future in aging?.J Hepatol. 2016; 65: 825-834Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Autophagy is a catabolic pathway in which the cellular contents are wrapped in the double-membrane autophagosomes and delivered to lysosomes for degradation.2Qian H. Chao X. Williams J. Fulte S. Li T. Yang L. Ding W.X. Autophagy in liver diseases: A review.Mol Aspects Med. 2021; 100973Crossref PubMed Scopus (42) Google Scholar Interestingly, stresses such as oxidative stress and DNA damage that trigger senescence also can activate autophagy or apoptosis. It is conceivable that the magnitude of the stresses may decide a cell should undergo autophagy, senescence, or apoptosis. Although both senescence and autophagy have been implicated in chronic liver diseases,1Aravinthan A.D. Alexander G.J.M. Senescence in chronic liver disease: Is the future in aging?.J Hepatol. 2016; 65: 825-834Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar,2Qian H. Chao X. Williams J. Fulte S. Li T. Yang L. Ding W.X. Autophagy in liver diseases: A review.Mol Aspects Med. 2021; 100973Crossref PubMed Scopus (42) Google Scholar the inter-relationship of autophagy and senescence in liver pathogenesis of autophagy-defective livers has not been studied. Mice with genetic deletion of autophagy-related genes, such as Atg5 or Atg7, develop liver injury, inflammation, fibrosis, and spontaneous adenoma.3Ni H.M. Woolbright B.L. Williams J. Copple B. Cui W. Luyendyk J.P. Jaeschke H. Ding W.X. Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy.J Hepatol. 2014; 61: 617-625Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar,4Khambu B. Huda N. Chen X. Antoine D.J. Li Y. Dai G. Köhler U.A. Zong W.X. Waguri S. Werner S. Oury T.D. Dong Z. Yin X.M. HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers.J Clin Invest. 2018; 128: 2419-2435Crossref PubMed Scopus (66) Google Scholar In this issue of Cellular and Molecular Gastroenterology and Hepatology, Huda et al5Huda N. Khambu B. Liu G. Nakatsumi H. Yan S. Chen X. Ma M. Dong Z. Nakayama K.I. Yin X.M. Senescence Connects Autophagy Deficiency to Inflammation and Tumor Progression in the Liver.Cell Mol Gastroenterol Hepatol. 2022; 14: 333-355Abstract Full Text Full Text PDF Scopus (3) Google Scholar investigated the temporal changes, possible mechanisms, and role of senescence in the pathogenesis of mouse livers with defective hepatic autophagy. They found that senescence markers, including β-galactosidase activity, p15/Cdkn2b, p21/Cdkn1a, and Cdkn3, as well as senescence-associated DNA damage, senescence-associated heterochromatic foci, and SASP, all were increased in liver-specific Atg7 knockout (L-Atg7 KO) mice in an age-dependent manner. Because L-Atg5 or L-Atg7 KO mice develop liver injury at 2 months old,3Ni H.M. Woolbright B.L. Williams J. Copple B. Cui W. Luyendyk J.P. Jaeschke H. Ding W.X. Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy.J Hepatol. 2014; 61: 617-625Abstract Full Text Full Text PDF PubMed Scopus ","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2022,"id":287406,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":967484,"name":"Sha Neisha Williams","orcid":"0009-0008-9400-7233","position":1,"is_corresponding":false},{"id":284312,"name":"Wen‐Xing Ding","orcid":"0000-0002-3167-5073","position":2,"is_corresponding":false},{"id":326046,"name":"Xiaowen Ma","orcid":"0000-0001-9324-0350","position":0,"is_corresponding":true}],"reference_count":8,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:30:01.051685Z","pmid":"35605640","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":[]}