Baicalein targets the Nrf2/Keap1 interaction and related stress pathways to mitigate drug-induced toxicity and reverse resistance in breast cancer: A review.

The cellular stress mediator Nrf2 and its negative regulator Keap1 are frequently dysregulated across breast cancer subtypes. As a master regulator of stress-related pathways, the Nrf2/Keap1 complex drives either cytoprotection or cell death, depending on the cellular context. Furthermore, its roles in promoting drug resistance and inflammation make it a highly promising therapeutic target. The natural flavonoid baicalein (BAI) has gained attention for its broad therapeutic potential, including protection against drug-induced toxicities and sensitization of drug-resistant breast cancers. We critically evaluated the biological action and protective effects of BAI against therapy-induced resistance mechanisms in BC. We also analyzed the protective effect of BAI against chemotherapy-induced multiorgan toxicities. We explored the context-dependent action of BAI on Nrf2 in normal and cancer cells, including antioxidant, anti-inflammatory, and prooxidant effects. We discussed the therapeutic potential of BAI against BC, including its ability to inhibit survival pathways and drug resistance mechanisms. We also reviewed the synergistic action of BAI with chemotherapeutic drugs in sensitizing BC cells to enhance cell death. We also reviewed recent updates on nanodelivery systems for BAI that potentially increase its solubility, bioavailability, and efficacy. This comprehensive review establishes a foundation for the design of BAI-based therapy regimens to mitigate drug resistance and improve clinical outcomes of BC patients.