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Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Notch1 signaling regulates innate immune-mediated inflammation in acute liver injury (ALI). However, the precise mechanism by which Notch1 governs macrophage polarization during ALI remains poorly understood. Methods: Wild-type (WT) mice received DAPT (10 mg\/kg) prior to acetaminophen (APAP)-induced ALI. In parallel, bone marrow-derived macrophages (BMMs) were pretreated with either the \u03b2-catenin inhibitor XAV939 or the activator SKL2001, exposed to DAPT, and then challenged with lipopolysaccharide (LPS). Liver injury and inflammation were evaluated by hematoxylin and eosin (H&amp;E) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry, immunofluorescence, quantitative real-time PCR (RT-PCR), and western blotting. Results: Unexpectedly, DAPT treatment exacerbated APAP-induced liver injury (AILI), resulting in more severe hepatocellular damage and inflammation than in controls. DAPT-treated macrophages exhibited enhanced pro-inflammatory cytokines expression and a shift toward an M1-like phenotype. Mechanistically, the \u03b2-catenin\/glycogen synthase kinase 3 beta (GSK3\u03b2) signaling pathway emerged as a pivotal regulator of macrophage polarization. Conclusions: Notch1 inhibition unexpectedly worsens AILI by amplifying macrophage-driven pro-inflammatory responses via \u03b2-catenin signaling. These findings highlight the Notch1\u2013\u03b2-catenin axis as a key regulator of hepatic macrophage function and a potential therapeutic target for sterile liver inflammation.<\/jats:p>","DOI":"10.31083\/fbl43853","type":"journal-article","created":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T04:43:39Z","timestamp":1760157819000},"source":"Crossref","is-referenced-by-count":3,"title":["Notch1 Inhibition Exacerbates APAP-Induced Liver Injury via \u03b2-Catenin and Macrophage Polarization"],"prefix":"10.31083","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1127-9364","authenticated-orcid":true,"given":"Tao","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Affiliated People\u2019s Hospital of Jiangsu University, 212001 Zhenjiang, Jiangsu, China"},{"name":"Zhenjiang School of Clinical Medicine With Nanjing Medical University, 212001 Zhenjiang, Jiangsu, China"},{"name":"Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0276-7027","authenticated-orcid":true,"given":"Jingjing","family":"Dai","sequence":"first","affiliation":[{"name":"Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8012-2166","authenticated-orcid":true,"given":"Junlan","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Affiliated People\u2019s Hospital of Jiangsu University, 212001 Zhenjiang, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6853-170X","authenticated-orcid":true,"given":"Yuyun","family":"Shao","sequence":"first","affiliation":[{"name":"Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9647-8847","authenticated-orcid":true,"given":"Xiao","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6741-1764","authenticated-orcid":true,"given":"Jiaying","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Li","sequence":"first","affiliation":[{"name":"Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7950-031X","authenticated-orcid":true,"given":"Ping","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8058-6838","authenticated-orcid":true,"given":"Longfeng","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2025,9,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Chalasani NP, Maddur H, Russo MW, Wong RJ, Reddy KR, Practice Parameters Committee of the American College of Gastroenterology. 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