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This study comprehensively investigates the role of alcohol-induced microbial alterations in ESCC progression. A retrospective analysis of 328 patients demonstrated that alcohol consumption markedly increases the risk of ESCC and boosts the expression of the proliferation marker Ki67. Patients with alcohol-related ESCC exhibited substantially higher blood microbiome diversity, characterized by the dominance of Gram-negative bacteria, and elevated serum lipopolysaccharides (LPS) levels. In a mouse model, alcohol consumption not only augmented tumor burden but also compromised gut barrier integrity, facilitating bacterial translocation. Significant elevations in Gram-negative bacteria, such as <jats:italic>Bacteroidales<\/jats:italic> in the blood and <jats:italic>Escherichia coli<\/jats:italic> in esophageal tissues, were observed. Mechanistically, alcohol and LPS synergistically activated pro-inflammatory pathways, including TNF, TLR, NF-\u03baB, and MAPK, which fueled ESCC cell proliferation. Meanwhile, LPS triggered necroptosis in normal esophageal epithelial cells. These findings reveal that alcohol-induced microbial dysbiosis in peripheral circulation and LPS-mediated inflammatory responses form a novel pathogenic mechanism in ESCC. Targeting Gram-negative bacteria and LPS could provide a promising therapeutic strategy for managing alcohol-related ESCC. Further research is urgently warranted to explore the interaction between microbial changes and the tumor microenvironment.<\/jats:p>","DOI":"10.1186\/s40164-025-00617-8","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T13:10:24Z","timestamp":1740489024000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Alcohol accelerates the development of esophageal squamous cell carcinoma through elevated Gram-negative bacteria in peripheral circulation"],"prefix":"10.1186","volume":"14","author":[{"given":"Zehua","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfen","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuyun","family":"Leng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meidong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,25]]},"reference":[{"issue":"10466","key":"617_CR1","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1016\/S0140-6736(24)02226-8","volume":"404","author":"H Yang","year":"2024","unstructured":"Yang H, Wang F, Hallemeier CL, Lerut T, Fu J. 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