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Therapeutic options for TNBC remain limited due to the absence of targetable hormone receptors. While BET bromodomain inhibitors (BBDIs) exhibit promising anticancer potential, the emergence of drug resistance presents a major challenge. Here, through leveraging single\u2010cell RNA sequencing (scRNA\u2010seq) data across continuous states of BBDI treatment in TNBC, this study conducts an extensive investigation into BBDI resistance, and develops two computational frameworks, FR20 and D\u2010FR20, to quantify BBDI resistance at single\u2010cell resolution and to screen potential BBDI re\u2010sensitizer drugs, respectively. The accuracy and scalability of FR20 are confirmed through rigorous evaluation in nine independent datasets. In addition, cellular dynamic changes and ferroptosis inhibition are revealed in the evolution of BBDI resistance. Experimental validation demonstrates that\n                    <jats:italic>GPX<\/jats:italic>\n                    4 overexpression significantly reduces drug sensitivity in TNBC cells. Furthermore, in vitro and in vivo experiments validate the ability of the small molecule filgotinib, identified by D\u2010FR20, to re\u2010sensitize BBDI and effectively eliminate resistant TNBC cells. Collectively, this study provides two computational frameworks for predicting BBDI resistance and candidate re\u2010sensitizer, as well as demonstrates the roles of ferroptosis in BBDI resistance, offering a promising avenue for TNBC treatment.\n                  <\/jats:p>","DOI":"10.1002\/advs.202513246","type":"journal-article","created":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T05:49:50Z","timestamp":1775281790000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Single\u2010Cell Computational Frameworks for Quantifying BET Bromodomain Inhibitor Resistance and Screening Re\u2010Sensitizer Drugs in Triple\u2010Negative Breast Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Haizhou","family":"Liu","sequence":"first","affiliation":[{"name":"Fujian Key Laboratory of Tumor Immunotherapy The First Affiliated Hospital Fujian Medical University  Fuzhou China"},{"name":"National Regional Medical 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Medicine Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Chen","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Tumor Immunotherapy The First Affiliated Hospital Fujian Medical University  Fuzhou China"},{"name":"National Regional Medical Center Binhai Campus of the First Affiliated Hospital Fujian Medical University  Fuzhou China"},{"name":"Department of Bioinformatics Fujian Key Laboratory of Medical Bioinformatics School of Medical Technology and Engineering Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Nanjing University of Aeronautics and Astronautics  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihong","family":"Wang","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of 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