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Hepatic macrophages play a primary role in the pathogenesis of alcoholic liver disease. Herein, we observed that SRA expression was significantly increased in the liver tissues of mice with alcohol-related liver injury. SRA-deficient (SRA\u2212\/\u2212) mice developed more severe alcohol-induced liver disease than wild-type mice. Enhanced liver inflammation existed in alcohol-challenged SRA\u2212\/\u2212 mice and was associated with increased Notch activation in hepatic macrophages compared with wild-type control animals. Mechanistically, SRA directly bound with Notch1 and suppressed its S-glutathionylation, thereby inhibiting Notch pathway activation. Further, we determined that the SRA interacted with thioredoxin-1 (Trx-1), a redox-active protein. SRA inhibited Trx-1 dimerization and facilitated the interaction of Trx-1 with Notch1. Application of a Trx-1-specific inhibitory agent during macrophage stimulation abolished SRA-mediated regulation of the Notch pathway and its downstream targets. In summary, our study revealed that SRA plays a critical role in macrophage inflammatory response by targeting Notch1 for its glutathionylation. SRA-mediated negative regulation of Notch activation might serve as a novel therapeutic strategy for alcohol-induced liver injury.<\/jats:p>","DOI":"10.1093\/jleuko\/qiad110","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T00:25:11Z","timestamp":1695169511000},"page":"322-333","source":"Crossref","is-referenced-by-count":2,"title":["Macrophage-expressed SRA ameliorates alcohol-induced liver injury by suppressing S-glutathionylation of Notch1 via recruiting thioredoxin"],"prefix":"10.1093","volume":"115","author":[{"given":"Lei","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Immunology, Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University , No.1023 South Shatai Road, Baiyun District, Guangzhou, Guangdong 510515, 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510515, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences, Southern Medical University , No.1023 South Shatai Road, Baiyun District, Guangzhou, Guangdong 510515, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences, Southern Medical University , No.1023 South Shatai Road, Baiyun District, Guangzhou, Guangdong 510515, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9726-8403","authenticated-orcid":false,"given":"Qingyun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University , No.106 Second Zhongshan 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