Abstract / Summary
Abstract Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation and has emerged as a promising therapeutic target in cancer. However, increasing evidence indicates that tumor cells develop adaptive mechanisms to evade ferroptosis, limiting the efficacy of ferroptosis-inducing therapies. While canonical antioxidant systems such as the glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis and ferroptosis suppressor protein 1 (FSP1) have been extensively studied, additional redox-buffering mechanisms remain incompletely understood. Recent studies suggest that metallothioneins (MTs), a family of cysteine-rich metal-binding proteins, function as a complementary redox-adaptive system that mitigates oxidative stress and suppresses lipid peroxidation. MTs are induced in response to ferroptosis-associated stress and contribute to therapy resistance by buffering reactive oxygen species and supporting intracellular thiol homeostasis. Evidence from multiple solid tumors and hematological malignancies indicates that MT upregulation may limit ferroptosis induction and promote tumor cell survival. AML serves as one representative example in which MT-mediated redox adaptation has recently been demonstrated. In this mini-review, I summarize current knowledge on ferroptosis regulation in cancer and propose that MTs represent a previously underappreciated component of the redox defense network. Targeting the MT–ferroptosis axis may provide a novel strategy to enhance the efficacy of ferroptosis-based cancer therapies.