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Its stabilized expression and prolonged activation significantly contribute to the development and progression of inflammatory diseases and malignancies within the digestive system. In the context of inflammation, HIF-1\u03b1 plays a pivotal role in the pathogenesis of various disorders\u2014including periodontitis, eosinophilic esophagitis, viral hepatitis, pancreatitis, and inflammatory bowel disease\u2014by modulating the expression of inflammatory mediators, driving cellular metabolic reprogramming, and influencing tissue barrier function. In terms of tumor biology, this review synthesizes pan-cancer analysis data to summarize the expression patterns of HIF-1\u03b1 in major gastrointestinal malignancies, including esophageal, gastric, pancreatic, hepatocellular, and colorectal cancers. It elucidates HIF-1\u03b1\u2019s role in directly promoting tumor cell proliferation, invasion, and drug resistance, while also remodeling the tumor microenvironment to regulate immune responses. We dissect how HIF-1\u03b1 cooperatively drives the formation of an immunosuppressive microenvironment, thereby influencing the efficacy of immunotherapy. This review aims to integrate the regulatory networks and molecular mechanisms of HIF-1\u03b1 in digestive system inflammation, tumors, and their immune microenvironment, ultimately providing novel theoretical foundations and strategic insights for targeted therapies and immune interventions in related diseases.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1772110","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T12:03:21Z","timestamp":1774958601000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["The central regulator HIF-1\u03b1 in digestive system pathologies: inflammation and cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Guoyou","family":"Gou","sequence":"first","affiliation":[{"name":"Zunyi Medical University","place":["Zunyi, 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