From molecular to microenvironmental reprogramming: Multi-target strategies of flavonoids to overcome paclitaxel resistance in triple-negative breast cancer.

BACKGROUND: Breast cancer is the most common malignancy in women. Triple-negative breast cancer (TNBC), due to a lack of effective targets, has a particularly poor prognosis. The efficacy of paclitaxel, a core chemotherapeutic drug, is often limited by multidrug resistance in tumor cells. Flavonoids, natural polyphenols with multi-pathway intervention properties, show significant potential for reversing this resistance, yet their clinical use is hindered by low bioavailability. Thus, understanding how Flavonoids overcome resistance and combining them with advanced delivery systems are key to developing new TNBC therapies. PURPOSE: This review systematically outlines the multi-dimensional mechanisms of paclitaxel resistance in TNBC and elucidates how Flavonoids reverse this resistance by regulating ferroptosis, key signaling pathways, epigenetic programs, and the immune microenvironment. It further discusses advanced delivery systems to facilitate clinical translation, providing a theoretical basis for developing effective, low-toxicity chemosensitization strategies against TNBC. METHODS: We systematically reviewed PubMed (PubMed), Web of Science (https://www.webofscience.com/), and ScienceDirect (http://www.sciencedirect.com/) databases, spanning relevant studies from 2005 to 2026. Article selection was performed in strict accordance with the PRISMA guidelines. Furthermore, manual screening and citation tracking were implemented based on pre-defined inclusion and exclusion criteria to ensure the accuracy and comprehensiveness of the study. RESULTS: TNBC resistance to paclitaxel is driven by ferroptosis evasion, pro-survival signaling, epigenetic reprogramming, and a "cold" tumor microenvironment. Flavonoids counteract this by inducing ferroptosis via the glutathione-glutathione peroxidase 4 (GSH-GPX4)/Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-related factor 2 (NRF2) axis inhibiting signaling networks, remodeling epigenetics, and immunomodulating the TME, thereby synergizing with paclitaxel. Additionally, advanced delivery systems, including prodrug self-assembly, metal-organic framework (MOF)-based carriers, and biomimetic targeting, significantly improve the bioavailability, targeting, and safety of the treatment. CONCLUSION: Complex TNBC paclitaxel resistance necessitates multi-target approaches. Flavonoids systematically dismantle resistance barriers and synergize with paclitaxel, while advanced delivery systems overcome pharmacokinetic limitations. Integrating these strategies offers a promising therapeutic solution, though further in vivo and clinical validation is required to confirm efficacy and safety.