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Here, we revealed that HECTD1 regulates IGF2BP3\u2010dependent HIF\u20101\u03b1 translation to promote Th17 cell glycolysis and differentiation and that HECTD1 expression correlates with IBD and CAC pathogenesis. T\u2010cell\u2010specific deletion of HECTD1 mitigated the severity of colitis and CAC in murine models. RNA\u2010seq revealed enrichment of Th17 differentiation, glycolysis\/gluconeogenesis, and HIF\u20101 signaling pathways among differentially expressed genes between HECTD1\u2010sufficient and HECTD1\u2010deficient CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Consistently, loss of HECTD1 suppressed Th17 cell differentiation both in vitro and in vivo, and suppressed glycolytic metabolism and HIF\u20101\u03b1 activity, revealing the mechanism underlying its protective effects against IBD and CAC. Mechanistically, HECTD1 potentiates m\n                    <jats:sup>6<\/jats:sup>\n                    A\u2010based HIF\u20101\u03b1 translation by mediating IGF2BP3 K63\u2010linked ubiquitination to promote the binding of IGF2BP3 with the translation initiation machinery of\n                    <jats:italic>Hif1a<\/jats:italic>\n                    mRNA. Reciprocally, HIF\u20101\u03b1 acts as a key transcription factor that promotes\n                    <jats:italic>Hectd1<\/jats:italic>\n                    gene expression, establishing a distinct positive feedback loop. Our findings highlight a self\u2010reinforcing feedback mechanism in which HECTD1 and HIF\u20101\u03b1 engage in mutual regulation to dictate Th17 cell fate and metabolic reprogramming, providing novel potential IBD and CAC treatments targeting HECTD1.\n                  <\/jats:p>","DOI":"10.1002\/advs.78339","type":"journal-article","created":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T14:51:11Z","timestamp":1792335071000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HECTD1 Directs HIF\u20101\u03b1 to Facilitate Intestinal Inflammation and Carcinogenesis via Promoting Th17 Differentiation and Glycolysis"],"prefix":"10.1002","author":[{"given":"Shuiyu","family":"Xu","sequence":"first","affiliation":[{"name":"Department of General Surgery Ruijin Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 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Hospital University of Electronic Science and Technology of China  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of General Surgery Ruijin Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of General Surgery Ruijin Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3054-9478","authenticated-orcid":false,"given":"Fang Xiu","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pathology Ruijin Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 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