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In this study, an in vivo screening system integrating genome\u2010wide short hairpin RNA library and next\u2010generation sequencing identifies six candidate metastasis suppressors, among which Homeobox D4 (HOXD4) shows the most pronounced effects. Clinicopathological analyses reveal significant HOXD4 downregulation in tumor tissues relative to adjacent normal tissues, with reduced expression strongly correlating with aggressive tumor features. Functional assays demonstrate that HOXD4 depletion enhances migration, invasion, and tumorsphere formation in HCT116 cells, while ectopic HOXD4 overexpression reverses these malignant phenotypes in SW620 cells. Mechanistically, HOXD4 suppresses epithelial\u2010mesenchymal transition (EMT) by directly binding to the promoter of Forkhead box Q1 (FOXQ1), a key driver of EMT and stemness, and thereby transcriptionally repressing its expression. Immunohistochemistry confirms an inverse correlation between HOXD4 and FOXQ1 expression in clinical specimens. Rescue experiments substantiate that HOXD4 exerts its metastasis\u2010suppressing functions via FOXQ1 regulation. Collectively, these findings not only establish an efficient platform for screening tumor metastasis suppressors, but also identify HOXD4 as a master transcriptional regulator of the FOXQ1\u2010EMT axis, providing a promising target for metastasis interception.<\/jats:p>","DOI":"10.1002\/advs.202520829","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T13:00:39Z","timestamp":1782478839000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genome\u2010Wide In Vivo RNAi Screening Identifies HOXD4 as a Tumor Metastasis Suppressor in Colorectal Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Zhi\u2010hua","family":"Ye","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010sen University Cancer Center  Guangzhou Guangdong China"},{"name":"Department\u00a0of Medical Oncology Center Zhongshan City People's Hospital  Zhongshan Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0850-0604","authenticated-orcid":false,"given":"Wen\u2010jing","family":"Luo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010sen University Cancer Center  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010sen University Cancer Center  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen\u2010di","family":"Shuai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010sen University Cancer Center  Guangzhou Guangdong China"},{"name":"Department of Oncology Qingdao Municipal Hospital  Qingdao Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010sen University Cancer Center  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You\u2010fa","family":"Duan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010sen University Cancer Center  Guangzhou Guangdong China"},{"name":"Guiyang Healthcare Vocational University Clinical and Rehabilitation College  Guiyang Guizhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010sen University Cancer Center  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun\u2010kai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department\u00a0of Medical Oncology Center Zhongshan City People's Hospital  Zhongshan Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlin","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010sen University Cancer Center  Guangzhou Guangdong China"},{"name":"Guangdong Provincial Key Laboratory of Tumor Targeted Drugs &amp; Guangzhou Enterprise Key Laboratory of Gene Medicine Guangzhou Doublle Bioproducts Co. 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