ABSTRACT Ferroptosis is a regulated, iron‐dependent form of cell death that has emerged as a promising therapeutic target for multiple cancers. However, its clinical translation faces significant challenges, particularly regarding precision and safety for cancer patients. Recent studies have identified RNA‐binding proteins (RBPs) as novel regulators of tumor ferroptosis, extending beyond the established biochemical hallmarks and core defense mechanisms of ferroptosis. This review focuses on the core machinery of ferroptosis and the canonical functions of RBPs in cancer biology. We further present evidence demonstrating that RBPs play a critical role in coordinating iron, lipid, and amino acid metabolism to influence ferroptosis, highlighting the complex interplay between RBPs and ferroptotic processes. Building on these insights, we explore therapeutic opportunities targeting the RBP‐ferroptosis axis from three perspectives: small molecules, synthetic lethality strategies, and drug delivery systems. Finally, we discuss the challenges and future prospects of RBP‐based ferroptosis therapeutic strategies in cancer. Overall, this review underscores the significant role of RBPs in tumor ferroptosis and lays the groundwork for precision oncology approaches guided by ferroptosis, moving beyond the classical biochemical hallmarks and core defense systems.
Chang et al. (Mon,) studied this question.