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This study aimed to explore the potential effect of hypoxia inducible factor-1\u03b1 (HIF-1\u03b1) on ferroptosis in intestinal epithelial cells (IECs) in UC. The relationship between ferroptosis and HIF-1\u03b1 was initially investigated using clinical UC colon samples. In vitro and in vivo models of acute intestinal inflammatory response were constructed using lipopolysaccharide (LPS) and dextran sulfate sodium (DSS), respectively. The effect of HIF-1\u03b1 on ferroptosis in UC was determined by establishing HIF-1\u03b1 overexpression (HIF1A-OE) or knockdown (shHIF1A) IEC lines, and the mechanism by which HIF-1\u03b1 mediated the transcription of glutathione peroxidase 4 (GPX4) was explored by combining Co-immunoprecipitation (Co-IP) and Chromatin immunoprecipitation-qPCR (ChIP-qPCR). The results indicated that ferroptosis was present in IECs from UC patients and colitis mice. Elevated expression of HIF-1\u03b1 ameliorated the secretion of inflammatory cytokines and ferroptosis in IECs in vitro. HIF-1\u03b1 inhibited ferroptosis by transcriptional activation of the\n                    <jats:italic>GPX4<\/jats:italic>\n                    gene in inflammatory IECs. HIF-1\u03b1 ameliorated the general conditions of mice and intestinal barrier dysfunction and by suppressing ferroptosis in IECs of mice through upregulating the expression of GPX4. In conclusion, ferroptosis occurred in the IECs of UC patients and colitis mice. HIF-1\u03b1 may improve UC by suppressing ferroptosis in IECs through regulating the transcription of GPX4.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-07883-8","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T02:20:03Z","timestamp":1753150803000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["HIF-1\u03b1 alleviates ferroptosis in ulcerative colitis by regulation of GPX4"],"prefix":"10.1038","volume":"16","author":[{"given":"Weitao","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanliang","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daxing","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongchi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siying","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huie","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiyong","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4133-9751","authenticated-orcid":false,"given":"Xiaoqing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"7883_CR1","doi-asserted-by":"publisher","first-page":"2652","DOI":"10.1056\/NEJMra2002697","volume":"383","author":"JT Chang","year":"2020","unstructured":"Chang JT. 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