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Background The very-long-chain fatty acid (VLCFA) elongation complex is a fundamental, four-component enzymatic machinery responsible for synthesizing VLCFAs via stepwise elongation of long-chain fatty acid precursors. Dysregulation of the VLCFA elongation pathway is implicated in various cancers and other diseases. However, mechanisms governing individual enzymes in this complex and their roles in tumorigenesis remain poorly understood, hindering targeted anti-tumor therapy development.Methods SubjectsPan-cancer expression datasets (VLCFA elongation complex genes).Colorectal cancer (CRC) tissues/cells (focus on TECR upregulation).MethodsSystematic gene expression analysis across cancers to identify TECR upregulation in CRC.Genetic knockdown of TECR -measured VLCFA synthesis and tumorigenicity.Atomic-resolution structure of the complex reveals the mechanisms of HACD and TECR.Identification and mutational disruption of the key HACD–TECR protein interface.Functional assays showing interface disruption inhibits CRC cell proliferation.Integrated structural and functional data to support rational inhibitor design (orthosteric TECR inhibitors or allosteric HACD–TECR disruptors).Results In this study, we systematically analyzed the expression profiles of VLCFA elongation complex components across multiple cancer types and identified trans-2-enoyl-CoA reductase (TECR) as being upregulated in colorectal cancer (CRC). Genetic ablation of TECR impaired VLCFA biosynthesis in CRC cells and significantly suppressed tumorigenic potential. Moreover, we determined the first atomic-resolution structure of a eukaryotic HACD–TECR complex, which elucidates the catalytic dehydration mechanism of 3-hydroxyacyl-CoA dehydratase (HACD) and the NADPH-dependent reduction mechanism of TECR. Notably, our structural and functional analyses uncovered a highly specific protein–protein interface between HACD and TECR that is essential for their functional coupling and substrate channeling. Disrupting the HACD–TECR interface robustly inhibited CRC cell proliferation. These findings reveal the structure and catalytic coordination of the HACD–TECR subcomplex, providing a basis for designing TECR orthosteric inhibitors or allosteric HACD–TECR disruptors as potential CRC therapies.Conclusions Overall, this study substantially advances our understanding of the VLCFA elongation subcomplex and its pathogenic role in CRC. The structural and functional insights presented herein will facilitate the development of mechanism-based, small-molecule or peptide therapeutics - either through direct enzyme inhibition or selective disruption of critical inter-subunit interactions. These findings will interest researchers in lipid metabolism, cancer biology, and drug discovery, and support the development of next-generation anticancer drugs.