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Adv."],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:p>Remodeling of fatty acid metabolism is increasingly recognized as a critical feature of tumor progression, yet the contribution of very long-chain fatty acid (VLCFA) remains incompletely understood. The elongation of VLCFAs, which is mediated by four consecutive enzymes in the endoplasmic reticulum (ER), has been implicated in tumor progression. However, the molecular mechanisms underlying VLCFA elongation enzymes and their specific contributions to tumorigenesis remain largely elusive. Here, we demonstrate that trans-2-enoyl-CoA reductase (TECR) is upregulated in colorectal cancer (CRC). Structural and biochemical analyses revealed a conserved catalytic mechanism for TECR-mediated trans-2-enoyl-CoA reduction. Moreover, we show that TECR forms a stable complex with 3-hydroxyacyl-CoA dehydratase (HACD), to cooperatively drive VLCFA elongation. A unique U-shaped loop in HACD is critical for recognizing TECR. Disruption of the HACD\u2013TECR interaction interface significantly suppresses CRC cell growth. Collectively, these findings elucidate the molecular mechanism of HACD\u2013TECR-mediated VLCFA elongation and suggest a potential therapeutic strategy for CRC treatment by modulating VLCFA metabolism.<\/jats:p>","DOI":"10.1126\/sciadv.aeh5593","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T18:01:07Z","timestamp":1786557667000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Molecular basis of HACD-TECR complex mediated very-long-chain fatty acid elongation reveal a potential target in colorectal cancer"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0982-385X","authenticated-orcid":true,"given":"Rui","family":"Lv","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200437, China."},{"name":"Shanghai Xuhui Central 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