Upregulation of CDO1 by theaflavin-3,3'-gallate induces apoptosis and inhibits cell proliferation in TNBC

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options due to the absence of targetable receptors. Theaflavin-3,3'-gallate (TF-3), a polyphenol abundant in black tea, has demonstrated anticancer activity across multiple cancer types, including prostate and ovarian cancers, suggesting its potential as a broad-spectrum antitumor agent. However, the specific mechanisms underlying its effects in breast cancer remain to be fully elucidated. In this study, we show that TF-3 significantly inhibits TNBC cell proliferation, migration, and colony formation while inducing apoptosis in a dose-dependent manner. Transcriptomic analysis revealed that these antitumor effects are accompanied by upregulation of cysteine dioxygenase type 1 (CDO1), suggesting its potential involvement. Metabolomic profiling demonstrated that TF-3 treatment profoundly reprograms the TNBC metabolome, with amino acid and lipid metabolism pathways being primary targets. Functional experiments showed that CDO1 knockdown partially attenuates TF-3 induced apoptosis, whereas CDO1 overexpression enhances caspase-3/9 activation, indicating a contributory rather than exclusive role for CDO1. Furthermore, bioinformatic analyses identified CDO1 as a potential diagnostic and prognostic biomarker, with its expression correlating with immune cell infiltration (particularly macrophages and T cells) in the tumor microenvironment; however, these associations are correlative and require experimental validation. Collectively, our findings establish TF-3 as a promising therapeutic candidate for TNBC and underscore the critical involvement of CDO1 in its antitumor effects, providing a foundation for future combination strategies targeting metabolism and immune modulation.