The effects of Palbociclib and Ferulic acid combination on cellular processes in breast cancer.

[UNLABELLED] Breast cancer remains a major cause of cancer-related morbidity and mortality worldwide, highlighting the urgent need for novel therapeutic approaches. In this study, we aimed to investigate the combined effects of Palbociclib (PLB), a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, and Ferulic Acid (FA), a natural antioxidant, on breast cancer cells (MCF-7 and MDA-MB231) as well as on non-tumorigenic breast epithelial cells (MCF-10 A). To this end, the effects of PLB and FA on cell viability, migration, cell cycle progression, oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial membrane potential (MMP), and apoptosis were evaluated. MTT assay results demonstrated that both agents, alone and in combination, significantly suppressed proliferation in cancer cells, whereas their impact on MCF-10 A cells was comparatively limited. In addition, oxidative stress and lipid peroxidation levels increased markedly in cancer cells following the combination treatment, while this increase was relatively restricted in MCF-10 A cells. MMP was significantly reduced in cancer cell lines under combination treatment, but was largely preserved in MCF-10 A cells. Molecular analyses revealed upregulation of ER stress markers (,,,,) and pro-apoptotic genes (,,), along with downregulation of the anti-apoptotic gene . Furthermore, phosphorylated retinoblastoma protein (pRB) levels decreased significantly, indicating enhanced cell cycle arrest and chemosensitivity. Taken together, these findings suggest that the combination of PLB and FA exerts a anti-cancer effect by simultaneously inducing oxidative and ER stress, disrupting mitochondrial integrity, and promoting apoptosis in breast cancer cells, while sparing non-tumorigenic cells. This selective cytotoxicity underscores the therapeutic potential of PLB and FA as a promising combinational strategy for breast cancer treatment.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s12672-026-04779-7.