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Solid tumors, including CRC, must adapt to intratumoral hypoxia and oxidative stress, but the tumor-cell programs that couple these pressures to metastatic competence remain unclear. Across human CRC cohorts and cell lines, HIF-1\u03b1 was coordinately upregulated and co-expressed with the metabolic effectors GLUT3 and fatty-acid synthase (FASN), most prominently in metastatic lesions. Using HIF-1\u03b1 (HRE), SREBP1 (SRE), and NRF2 (ARE) transcriptional reporters, we identified HRE-high and SRE-high CRC subpopulations with enhanced clonogenicity and invasion that drove accelerated tumor growth and increased lung metastatic burden across multiple CRC models. Mechanistically, IGF1 and insulin signaling through IGF1R and AKT-mTOR increased HIF-1\u03b1 and induced FASN and GLUT3, enabling lipogenic, glycolytic, and antioxidant programs to withstand hypoxic and oxidative stress. HIF-1\u03b1 engaged an HRE-containing proximal region of the human FASN promoter independently of SREBP1. Stress assays revealed functional specialization: FASN promoted NRF2-associated antioxidant capacity and resistance to oxidative injury, whereas GLUT3 preferentially supported hypoxia tolerance. In vivo, lipid nanoparticle\u2013encapsulated echinomycin rapidly suppressed HRE, SRE, and ARE activity, reduced peri-hypoxic induction of FASN and GLUT3, inhibited tumor growth, and eliminated lung metastasis. These findings define a growth factor\u2013responsive, HIF-1\u03b1-centered stress-adaptive state and highlight HIF-1\u03b1 transcriptional activity as a therapeutic target in metastatic CRC.<\/jats:p>","DOI":"10.1038\/s41388-026-03738-4","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T05:51:11Z","timestamp":1780465871000},"page":"2671-2682","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["HIF-1\u03b1 integrates lipogenic FASN and glycolytic GLUT3 to overcome intratumor oxidative and hypoxic stress for colorectal cancer metastasis"],"prefix":"10.1038","volume":"45","author":[{"given":"Yunyi","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyi","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Bailey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gong","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6218-1885","authenticated-orcid":false,"given":"Peng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunrong","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6340-4382","authenticated-orcid":false,"given":"Jean-Pierre","family":"Raufman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4749-3768","authenticated-orcid":false,"given":"Yin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4565-4780","authenticated-orcid":false,"given":"Yan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"3738_CR1","first-page":"394","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 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