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Using a self\u2010established drug combination prediction platform, we identified a strong synergy between the CDK4\/6 inhibitor palbociclib and the natural compound curcumin across both HR+\/HER2\u2212 and TNBC models, an effect that was also observed with ribociclib. Mechanistically, the combination led to a collapse of redox homeostasis. Despite upregulating transcriptional antioxidant responses, the treatment downregulated critical ROS\u2010detoxifying enzymes (e.g., GPX4) and depleted glutathione. This imbalance induced lethal oxidative stress, lipid peroxidation, and extensive DNA damage. Furthermore, excessive ROS accumulation contributed to suppression of epithelial\u2010mesenchymal transition (EMT) and reduced migratory and invasive phenotypes. The antioxidant N\u2010acetylcysteine (NAC) attenuated both cytotoxicity and migration inhibition, supporting a central role for ROS in these effects. Together, these findings identify a redox\u2010based mechanism underlying the combination and provide a rationale for further preclinical evaluation in HR+\/HER2\u2212 breast cancer and TNBC.<\/jats:p>","DOI":"10.1111\/cas.70557","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T02:58:52Z","timestamp":1792378732000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>CDK4<\/scp>\n                    \/6 Inhibitors and Curcumin Synergistically Suppress\n                    <scp>HER2<\/scp>\n                    \u2212 Breast Cancer via Lethal\n                    <scp>ROS<\/scp>\n                    and Inhibition of Metastasis"],"prefix":"10.1111","author":[{"given":"Chenyu","family":"Wang","sequence":"first","affiliation":[{"name":"School of Medicine, Institute of Infection, Immunology and Tumor Microenvironment Wuhan University of Science and Technology  Wuhan 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