Abstract
Cancer remains a formidable global health challenge, with therapeutic resistance and disease relapse frequently attributed to the persistence of a resilient subpopulation of cells known as cancer stem cells (CSCs). These cells, characterized by self-renewal capacity, continuous proliferation, and multi-lineage differentiation potential, drive tumorigenesis, metastasis, and evade conventional therapies. Traditional cancer treatments often fail to eradicate CSCs, leading to their enrichment post-therapy and subsequent tumor recurrence. This comprehensive review explores two innovative and interconnected therapeutic paradigms for targeting CSCs: ferroptosis and metabostemness. Ferroptosis, an iron-dependent form of regulated cell death distinct from apoptosis, offers a promising avenue to overcome apoptosis resistance prevalent in many cancers, including CSCs, by inducing lethal lipid peroxidation. Concurrently, “metabostemness” describes the unique metabolic reprogramming of CSCs, encompassing alterations in glucose, lipid, and amino acid metabolism, which are critical for maintaining their stemness, survival, and resistance to treatment. This review synthesizes the current understanding of the molecular mechanisms underlying ferroptosis and metabostemness in CSCs, highlighting emerging small-molecule strategies designed to exploit these vulnerabilities. The discussion includes direct ferroptosis inducers and compounds that sensitize CSCs to ferroptosis by disrupting their aberrant metabolic pathways. Furthermore, the synergistic potential of combining ferroptosis induction with metabolic inhibitors to enhance therapeutic efficacy and circumvent drug resistance is explored. Finally, the significant challenges in clinical translation, including issues of specificity, systemic toxicity, and tumor heterogeneity, are addressed, while proposing advanced drug delivery systems and integrated multi-omics approaches as crucial future directions for realizing the full potential of these novel anti-CSC strategies in precision oncology.