Ferroptosis as a promising targeted therapy for triple negative breast cancer (Jun, 10.1007/s10549-024-07387-7, 2024)

PurposeTriple negative breast cancer (TNBC) is a challenging subtype characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Standard treatment options are limited, and approximately 45% of patients develop distant metastasis. Ferroptosis, a regulated form of cell death triggered by iron-dependent lipid peroxidation and oxidative stress, has emerged as a potential targeted therapy for TNBC.MethodsThis study utilizes a multifaceted approach to investigate the induction of ferroptosis as a therapeutic strategy for TNBC. It explores metabolic alterations, redox imbalance, and oncogenic signaling pathways to understand their roles in inducing ferroptosis, characterized by lipid peroxidation, reactive oxygen species (ROS) generation, and altered cellular morphology. Critical pathways such as Xc-/GSH/GPX4, ACSL4/LPCAT3, and nuclear factor erythroid 2-related factor 2 (NRF2) are examined for their regulatory roles in ferroptosis and their potential dysregulation contributing to cancer cell survival and resistance.ResultsInhibiting ferroptosis has been shown to inhibit tumor growth, enhance the efficacy of conventional therapies, and overcome drug resistance in TNBC. Lipophilic antioxidants, GPX4 inhibitors, and inhibitors of the Xc- system have been demonstrated to be potential ferroptosis inducers. Additionally, targeting the NRF2 pathway and exploring other ferroptosis regulators, such as ferroptosis suppressor protein 1 (FSP1), and the PERK-eIF2 alpha-ATF4-CHOP pathway, may offer novel therapeutic avenues.ConclusionFurther research is needed to understand the mechanisms, optimize therapeutic strategies, and evaluate the safety and efficacy of ferroptosis-targeted therapies in TNBC treatment. Overall, targeting ferroptosis represents a promising approach to improving treatment outcomes and overcoming the challenges posed by TNBC.