Research Progress on Active Ingredients of Traditional Chinese Medicine Against Triple-Negative Breast Cancer by Targeting Key Ferroptosis Pathways

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited treatment options and poor prognosis. Recent research has highlighted ferroptosis, an iron-dependent cell death process driven by lipid peroxidation, as a promising therapeutic target. TNBC exhibits inherent susceptibility to ferroptosis due to dysregulated iron metabolism (e.g., TfR1 overexpression), rewired lipid metabolism (e.g., ACSL4/LPCAT3 activation), and impaired antioxidant defenses (e.g., GPX4 suppression). Active ingredients derived from Traditional Chinese Medicine (TCM) leverage multi-target mechanisms to synergistically induce ferroptosis through three core strategies: (1) disrupting redox homeostasis via System Xc⁻/GSH/GPX4 axis inhibition (“Clearing Toxicity”); (2) promoting iron overload and lipid peroxidation by modulating iron-lipid metabolic networks (“Removing Stasis”); and (3) remodeling the immunosuppressive tumor microenvironment to synergize immunity with ferroptosis (“Reinforcing Healthy Qi”). This approach aligns with TCM theory in addressing “deficiency of healthy qi and toxicity-stasis. “ Nanocarriers and combination therapies further enhance precision and efficacy. This review summarizes these advances and suggests that future efforts should focus on mechanistic depth, subtype-specific targeting, and clinical translation to advance ferroptosis-based TCM strategies against TNBC.