{"doi":"10.1002/hep.32152","title":"Aging exaggerates acute‐on‐chronic alcohol‐induced liver injury in mice and humans by inhibiting neutrophilic sirtuin 1‐C/EBPα‐miRNA‐223 axis","abstract":"BACKGROUND AND AIMS: Aging exacerbates liver neutrophil infiltration and alcohol-associated liver disease (ALD) in mice and humans, but the underlying mechanisms remain obscure. This study aimed to examine the effect of aging and alcohol consumption on neutrophilic Sirtuin 1 (SIRT1) and microRNA-223 (miR-223), and their contribution to ALD pathogeneses. APPROACH AND RESULTS: Young and aged myeloid-specific Sirt1 knockout mice were subjected to chronic-plus-binge ethanol feeding. Blood samples from healthy controls and patients with chronic alcohol drinking who presented with acute intoxication were analyzed. Neutrophilic Sirt1 and miR-223 expression were down-regulated in aged mice compared with young mice. Deletion of the Sirt1 gene in myeloid cells including neutrophils exacerbated chronic-plus-binge ethanol-induced liver injury and inflammation and down-regulated neutrophilic miR-223 expression. Immunoprecipitation experiments revealed that SIRT1 promoted C/EBPα deacetylation by directly interacting with C/EBPα, a key transcription factor that controls miR-223 biogenesis, and subsequently elevated miR-223 expression in neutrophils. Importantly, down-regulation of SIRT1 and miR-223 expression was also observed in circulating neutrophils from middle-aged and elderly subjects compared with those from young individuals. Chronic alcohol users with acute intoxication had a reduction in neutrophilic SIRT1 expression in young and middle-aged patients, with a greater reduction in the latter group. The neutrophilic SIRT1 expression correlated with neutrophilic miR-223 and serum alanine transaminase levels in those patients. CONCLUSIONS: Aging increases the susceptibility of alcohol-induced liver injury in mice and humans through the down-regulation of the neutrophilic SIRT1-C/EBPα-miR-223 axis, which could be a therapeutic target for the prevention and/or treatment of ALD.","journal":"Hepatology","year":2021,"id":151941,"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":79,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9606,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":226856,"name":"Yong He","orcid":"0009-0006-8681-5287","position":1,"is_corresponding":false},{"id":645836,"name":"Dong Ding","orcid":"0000-0001-5232-7396","position":2,"is_corresponding":false},{"id":645837,"name":"Aoyuan Cui","orcid":"0000-0003-2037-9241","position":3,"is_corresponding":false},{"id":645838,"name":"Huarui Bao","orcid":"0000-0002-8313-7787","position":4,"is_corresponding":false},{"id":251605,"name":"Jing Ma","orcid":"0000-0002-2671-3792","position":5,"is_corresponding":false},{"id":243196,"name":"Xin Hou","orcid":"0000-0002-5980-5925","position":6,"is_corresponding":false},{"id":243201,"name":"Yu Li","orcid":"0000-0001-6910-5933","position":7,"is_corresponding":false},{"id":239662,"name":"Dechun Feng","orcid":"0000-0001-7485-762X","position":8,"is_corresponding":false},{"id":241287,"name":"Xiaoling Li","orcid":"0000-0001-5920-7784","position":9,"is_corresponding":false},{"id":242909,"name":"Suthat Liangpunsakul","orcid":"0000-0002-6504-8123","position":10,"is_corresponding":false},{"id":226858,"name":"Bin Gao","orcid":"0000-0002-0505-2972","position":11,"is_corresponding":false},{"id":105553,"name":"Hua Wang","orcid":"0000-0002-2605-5697","position":12,"is_corresponding":false},{"id":244217,"name":"Ruixue Ren","orcid":null,"position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-18T23:43:22.562252Z","pmid":"34510484","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":[]}