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Bufalin is a bufadienolides compound with potential anti\u2010cancer effects. This study shows that bufalin inhibits malignant proliferation of MDA\u2010MB\u2010231 and MCF\u20107 cells and protects mice against breast cancer. Of note, GTF3C4 was identified as the target protein by Limited Proteolysis\u2010Mass Spectrometry. GTF3C4 is overexpressed in breast cancer and associated with poor prognosis. RNA sequencing analysis reveals that the PI3K\/AKT signaling pathway is a key contributor. Using cell thermal shift assays, drug affinity response target stability assays, and surface plasmon resonance, it was verified that bufalin can specifically bind to GTF3C4. Bufalin reduces GTF3C4 protein levels in vivo and in vitro, effectively inhibiting breast cancer progression by suppressing the PI3K\/AKT signaling pathway. After the knockdown of GTF3C4, the PI3K\/AKT signaling pathway is also suppressed, thereby inhibiting the proliferation of breast cancer cells and promoting apoptosis. Single\u2010cell RNA sequencing results indicated that bufalin reduces the proportions of macrophages, neutrophils, and monocytes, and affects the strength of receptor\u2010ligand signals between cells. Collectively, this study demonstrates that bufalin targets GTF3C4 to inhibit the PI3K\/AKT pathway and remodels the tumor microenvironment, thereby hindering the malignant progression of breast cancer.<\/jats:p>","DOI":"10.1002\/advs.202507008","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T12:38:37Z","timestamp":1770381517000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Bufalin Inhibits the PI3K\/AKT Pathway by Targeting GTF3C4 to Impede Breast Cancer Progression"],"prefix":"10.1002","volume":"13","author":[{"given":"Siyu","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Clinical Chinese Pharmacy School of Chinese Materia Medica Beijing University of Chinese Medicine  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Clinical Chinese 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