Ferroptosis in multiple myeloma: molecular mechanisms and therapeutic opportunities

Multiple myeloma (MM) is a hematologic malignancy driven by clonal plasma-cell proliferation and remains largely incurable owing to disease relapse and acquired drug resistance. Ferroptosis, an iron-dependent form of regulated cell death characterized by excessive lipid peroxidation, has emerged as a potential therapeutic target in cancer and is increasingly implicated in MM biology. Unlike apoptosis and other classical cell death pathways, ferroptosis is closely associated with dysregulated iron metabolism, oxidative stress, and lipid peroxidation, all of which are key features of MM biology. This review first outlines the molecular mechanisms of ferroptosis and then summarizes current evidence linking ferroptosis to MM progression, therapeutic resistance, and emerging therapeutic strategies. In addition, current therapeutic strategies targeting ferroptosis are discussed, including inhibition of system Xc-, direct targeting of GPX4, modulation of iron metabolism, and their potential synergistic effects with existing anti-myeloma therapies. Finally, the major challenges associated with clinical translation are highlighted, together with future directions for biomarker development and ferroptosis-based therapeutic strategies. Collectively, ferroptosis represents a promising therapeutic concept for exploiting redox and metabolic vulnerabilities in MM. Nevertheless, current knowledge is derived predominantly from preclinical studies, and successful clinical translation will require improved tumor selectivity, rigorous safety evaluation, and biomarker-guided patient stratification.