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Despite substantial progress made at the genomic and transcriptomic levels, the detailed interplay among mRNA, proteins, and protein modifications as well as the corresponding actionable targets remained poorly explored. Here, we developed bioGraph, a biologically informed graph learning method designed to systematically identify proteo-transcriptomic networks from transcriptomic, proteomic, and phosphoproteomic data. By incorporating genetic interaction priors into a unique three-layered heterogeneous graph, bioGraph revealed functional intra-omic, inter-omic, and cross-omic regulatory networks with prognostic relevance, including previously overlooked interactions modulating cancer hallmarks. We introduced a multi-omic gene set variation analysis score to quantify the network activity. We applied bioGraph to pan-cancer datasets and identified trans-omic regulatory hub genes undetectable by conventional methods. MAP4 emerged as a marker associated with tumor growth and malignant behaviors, validated via external datasets and tumor cell line assays, demonstrating its therapeutic potential. Our findings establish bioGraph as a new tool for identifying proteo-transcriptomic networks and gene targets with rapidly expanding underutilized multi-omic resources.<\/jats:p>","DOI":"10.1093\/nar\/gkag386","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T11:29:04Z","timestamp":1776166144000},"source":"Crossref","is-referenced-by-count":0,"title":["Discovering proteo-transcriptomic networks via biologically informed heterogeneous graph learning"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9453-2651","authenticated-orcid":false,"given":"Jingxian","family":"Duan","sequence":"first","affiliation":[{"name":"Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055 ,","place":["China"]},{"name":"Faculty of Biomedical Engineering, Shenzhen University of Advanced Technology , Shenzhen 518107 ,","place":["China"]},{"name":"Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, State Key Laboratory of Biomedical Imaging Science and System , Shenzhen 518055 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaou","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radiology, Beijing Tiantan Hospital , Beijing 100070 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongling","family":"Pei","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, the First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zijian","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory & Center for Molecular Imaging and Translational Medicine, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University , Xiamen 361005 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanshen","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingran","family":"Deng","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055 ,","place":["China"]},{"name":"Faculty of Biomedical Engineering, Shenzhen University of Advanced Technology , Shenzhen 518107 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haofei","family":"Ma","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055 ,","place":["China"]},{"name":"Faculty of Biomedical Engineering, Shenzhen University of Advanced Technology , Shenzhen 518107 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055 ,","place":["China"]},{"name":"Faculty of Biomedical Engineering, Shenzhen University of Advanced Technology , Shenzhen 518107 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeyu","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, the First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zilong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, the First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5799-653X","authenticated-orcid":false,"given":"Shifu","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055 ,","place":["China"]},{"name":"HaploX Biotechnology Co. 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