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Here, we identify Tumor necrosis factor receptor superfamily member 19 (TNFRSF19) as an epigenetically silenced gene that critically regulates doxorubicin response. Integrative analyses of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and clinical cohorts reveal that high TNFRSF19 expression predicts superior pathological complete response and improved survival in doxorubicin\u2010treated TNBC patients. Mechanistically, TNFRSF19 binds the kinase domain of TGFBR1 via its intracellular domain, disrupting TGFBR1\u2013SMAD3 complex formation and thereby inhibiting SMAD3 phosphorylation, nuclear translocation, and transcriptional activation of PTEN\u2010induced putative kinase 1 (PINK1). This suppresses PINK1\/Parkin\u2010mediated mitophagy, contributing to mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and amplified DNA damage upon doxorubicin treatment. Notably, TNFRSF19 is downregulated in TNBC due to DNA hypermethylation, and decitabine restores its expression via promoter demethylation, thereby enhancing the therapeutic efficacy of doxorubicin in vitro and in vivo. Collectively, these findings establish TNFRSF19 as a critical epigenetic regulator of mitophagy, highlighting its potential as a predictive biomarker for doxorubicin response and a therapeutic target for sensitizing TNBC to doxorubicin.<\/jats:p>","DOI":"10.1002\/advs.77529","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T04:57:25Z","timestamp":1788238645000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Reactivation of TNFRSF19 Suppresses Mitophagy and Sensitizes Triple\u2010Negative Breast Cancer to Doxorubicin"],"prefix":"10.1002","author":[{"given":"Shiyang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Thyroid and Breast Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 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Science and Technology Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7754-2495","authenticated-orcid":false,"given":"Zhengwei","family":"Gui","sequence":"additional","affiliation":[{"name":"Department of Thyroid and Breast Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zonghong","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Thyroid and Breast Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun","family":"Ieong","sequence":"additional","affiliation":[{"name":"Department of Thyroid and Breast Surgery Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 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