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

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.