NRF2/SLC7A11/GPX4 Antioxidant Axis Suppression by Camel Milk Whey Protein Sensitizes MCF-7 Breast Cancer Cells to Cisplatin

Chemoresistance in breast cancer remains a major clinical challenge, fueled by robust antioxidant defenses that neutralize cisplatin-induced oxidative stress through the NRF2/SLC7A11/GPX4 pathway in luminal breast cancer cells. This study examined camel milk whey protein (CMP), a bioactive fraction rich in lactoferrin and antioxidant peptides, as a redox-modulating chemosensitizer to boost cisplatin efficacy in MCF-7 cells while simultaneously assessing treatment selectivity in non-tumorigenic MCF-12A mammary epithelial cells. Cells were treated for 24 h with CMP (at 200 and 600 ng/mL, designated as P1 and P2) and cisplatin (25 µM), both individually and in combination. Cell viability was evaluated via the MTT assay, and the mRNA expression levels of NRF2, GPX4, and SLC7A11 were quantified using RT-qPCR. Bliss independence synergy analysis was applied to the MTT datasets, and a protein–protein interaction network was constructed via STRING (v12.0). Furthermore, the clinical significance of the NRF2/SLC7A11/GPX4 axis was explored through Kaplan–Meier survival analysis (using KM Plotter), alongside genomic profiling via cBioPortal (TCGA PanCancer Atlas). Co-treatment with CMP and cisplatin significantly diminished MCF-7 cell viability compared to single-agent treatments, driven by the coordinated downregulation of NRF2, SLC7A11, and GPX4. Bliss independence modeling confirmed synergistic cytotoxicity for both the P1 + Cis and P2 + Cis combinations. Conversely, MCF-12A cells showed no intrinsic cytotoxicity (CC50 > 600 ng/mL) and displayed a distinct transcriptional profile following cisplatin exposure, marked by the upregulation of GPX4 and SLC7A11. In silico evaluations further reinforced the clinical relevance of this axis, revealing that elevated NRF2 and SLC7A11 expression correlates with poor relapse-free survival and recurrent genomic alterations across breast cancer cohorts. Ultimately, these results demonstrate that CMP disrupts the NRF2/SLC7A11/GPX4 antioxidant axis in cancer cells, offering a promising, selective strategy to enhance cisplatin sensitivity while safeguarding healthy tissues.