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Here, we identify the pseudokinase TRIB3 as a key mediator of the metabolic adaptation of hepatocellular carcinoma (HCC) cells to limiting glutamine availability. TRIB3 is upregulated under glutamine deprivation in a c\u2010Jun\u2010dependent manner, functioning in the nucleus to safeguard DNA repair fidelity, allowing the timely resolution of DNA damage and preventing replication catastrophe. TRIB3 binds to G\u2010quadruplex DNA (G4\u2010DNA) structures throughout the genome, recruiting the helicase DDX5 to resolve them as a cooperative functional complex. Depleting TRIB3 or DDX5 in HCC cells leads to exaggerated G4\u2010DNA accumulation and heightened DNA damage associated with the downregulation of DNA damage repair (DDR) pathways. We illustrate this effect on homologous recombination (HR) pathway genes, finding that TRIB3\u2010DDX5 prevents G4\u2010DNA accumulation at the\n                    <jats:italic>BRCA1<\/jats:italic>\n                    and\n                    <jats:italic>RAD51AP1<\/jats:italic>\n                    promoter regions that would otherwise suppress transcription. In vivo, TRIB3 silencing suppresses HCC xenograft growth, patently increasing DNA damage and apoptosis when mice were maintained on glutamine\u2010deficient diets. Clinically, TRIB3 is overexpressed in HCC and correlates with poor prognosis. Our results propose the TRIB3\u2010DDX5\u2010G4 axis as a therapeutic target in HCC and other TRIB3\u2010high malignancies.\n                  <\/jats:p>","DOI":"10.1002\/advs.202520798","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T22:17:05Z","timestamp":1773008225000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Glutamine Deprivation Triggers Tribbles Homolog 3 Dependent G\u2010Quadruplex Resolution to Maintain DNA Repair and Tumor Survival"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6254-8410","authenticated-orcid":false,"given":"Qiang","family":"Ji","sequence":"first","affiliation":[{"name":"Translational Research Institute of Henan Provincial People's Hospital and School of Basic Medical Sciences Henan University  Zhengzhou 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