CDK4 /6 Inhibitors and Curcumin Synergistically Suppress HER2 − Breast Cancer via Lethal ROS and Inhibition of Metastasis

ABSTRACT CDK4/6 inhibitors represent a key therapy for HR+/HER2− breast cancer, yet resistance and limited efficacy in triple‐negative breast cancer (TNBC) remain significant challenges. Using a self‐established drug combination prediction platform, we identified a strong synergy between the CDK4/6 inhibitor palbociclib and the natural compound curcumin across both HR+/HER2− 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‐detoxifying 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‐mesenchymal transition (EMT) and reduced migratory and invasive phenotypes. The antioxidant N‐acetylcysteine (NAC) attenuated both cytotoxicity and migration inhibition, supporting a central role for ROS in these effects. Together, these findings identify a redox‐based mechanism underlying the combination and provide a rationale for further preclinical evaluation in HR+/HER2− breast cancer and TNBC.