Targeting ferroptosis in cancer: molecular mechanisms and emerging therapeutic strategies

Ferroptosis, an iron-dependent form of regulated cell death characterized by the lethal accumulation of lipid peroxides, has emerged as a pivotal pathway in cancer biology and a promising therapeutic target. This review synthesizes the core molecular machinery governing ferroptosis, detailing the critical roles of iron metabolism through systems like transferrin/transferrin receptor 1 and ferritinophagy, the cystine/glutamate antiporter system (Xc − )/glutathione/GPX4 axis, and the recently discovered FSP1/CoQ10 pathway. We further explore the intricate interplay between lipid peroxidation, amino acid metabolism, and mitochondrial dysfunction, highlighting how their convergence dictates cellular susceptibility to ferroptotic death. The therapeutic potential of inducing ferroptosis in oncology is extensively reviewed, encompassing classic small-molecule inducers (e.g., erastin, RSL3, sorafenib) that target these key pathways. A significant focus is placed on the cutting-edge application of nanotechnology, discussing how various nanoparticles, including iron-based and organic systems, can potently induce ferroptosis through Fenton reactions, glutathione depletion, and targeted drug delivery, thereby overcoming traditional chemoresistance. We also introduce cold atmospheric plasma (CAP) as an emerging physical inducer of ferroptosis. Moreover, we examine the dynamic crosstalk between ferroptosis and the tumor immune microenvironment, particularly how CD8 + T cells and tumor-associated macrophages can modulate or respond to ferroptotic signals. Beyond summarizing the molecular basis of ferroptosis, this review critically integrates emerging advances in biomarker discovery, nanotechnology-enabled therapeutic strategies, and translational oncology to provide a clinically oriented perspective on ferroptosis-based cancer therapy. By highlighting biomarker-guided patient stratification, mechanisms of therapeutic resistance, and the principal challenges limiting clinical implementation, including tumor heterogeneity, off-target toxicity, pharmacokinetic constraints, and drug delivery barriers, this review provides a comprehensive framework for the rational development of precision oncology strategies targeting ferroptosis and identifies key priorities for future clinical translation.