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A comprehensive understanding of the mechanisms underlying metastasis in CRC is essential for advancing treatment strategies. Through integrated bioinformatics analysis of mRNA expression profiles and epigenetic modifiers, we identified SMYD3 as the top differentially expressed histone modifier in CRC. Clinically, SMYD3 overexpression significantly associates with poor prognosis and enhances metastatic potential. Utilizing immunoprecipitation-mass spectrometry, we discovered RACK1 as a novel SMYD3-interacting protein. Subsequent mechanistic studies revealed a tripartite interaction network: SMYD3 recruits SMAD3 through RACK1-mediated scaffolding, facilitating transcriptional activation of the downstream effector TSKU. Notably, RACK1 depletion disrupts SMYD3-SMAD3 complex formation, establishing the critical role of this axis in metastasis regulation. Consequently, inhibiting the SMYD3-SMAD3 interaction may represent a promising therapeutic strategy for addressing CRC metastasis. In conclusion, targeting the SMYD3-RACK1-SMAD3 transcriptional complex presents a viable approach for the treatment of CRC metastasis.<\/jats:p>","DOI":"10.1186\/s12964-026-02687-5","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T04:46:43Z","timestamp":1770094003000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SMYD3 synergises with RACK1 to promote colorectal cancer lung metastasis by recruiting SMAD3"],"prefix":"10.1186","volume":"24","author":[{"given":"Xiaoming","family":"Bai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siqi","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haimei","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yadi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengxi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyuan","family":"Chu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yitian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zengjie","family":"Lei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"issue":"10449","key":"2687_CR1","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/S0140-6736(24)00360-X","volume":"404","author":"C Eng","year":"2024","unstructured":"Eng C, Yoshino T, Ru\u00edz-Garc\u00eda E, Mostafa N, Cann CG, O\u2019Brian B, et al. 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