m6A methylation in ferroptosis regulation: mechanisms, targets, and therapeutic interventions

The molecular regulatory mechanism underlying the interaction between m6A and ferroptosis involves m6A methylation through writer, eraser, and reader proteins, whereas the core mechanism of ferroptosis involves primarily iron metabolism homeostasis, redox balance, and lipid peroxidation regulation. m6A methylation can induce alterations at the protein level by modifying ferroptosis-associated RNAs. • Although research on m6A modifications and ferroptosis continues to expand, there is a scarcity of review articles that systematically integrate their regulatory mechanisms . This review addresses this gap by comprehensively summarizing molecular targets associated with m6A and ferroptosis across multiple pathological contexts, with particular emphasis on their dual regulatory roles in oncological settings. By evaluating relevant targeted therapeutic agents , we establish a conceptual framework to advance the translation of basic research findings into clinical applications. The dynamic crosstalk between N6-methyladenosine (m6A) RNA methylation and ferroptosis is pivotal for understanding disease pathogenesis. As the most abundant form of eukaryotic mRNA modification, m6A methylation guides RNA metabolism through writers, erasers, and readers. Ferroptosis, an iron-dependent and lipid peroxidation-driven form of cell death, occurs under conditions including dysregulated iron metabolism, compromised antioxidant defences, and lipid peroxidation. This review highlights recent progress in basic research and proposes potential therapeutic targets for diseases of different systems while also addressing current drugs and challenges. m6A RNA modification is governed by three types of effector proteins—writers, erasers, and readers—while the molecular mechanisms governing ferroptosis involve three interconnected biological axes: iron metabolism homeostasis, redox balance, and lipid peroxidation dynamics. Studies have indicated that m6A methylation regulates the expression of ferroptosis-related proteins, thus influencing tumorigenesis, progression and pathogenesis. This review also summarizes currently available agents targeting m6A-related targets as well as those associated with both m6A and ferroptosis, aiming to highlight their potential for clinical applications.