Epitranscriptomic RNA Modifications in Human Disease: Cooperative Networks, Molecular Mechanisms, and Therapeutic Opportunities

Epitranscriptomic RNA modifications form a dynamic regulatory layer that shapes gene expression and cellular function. While N6-methyladenosine (m 6 A) has been extensively studied, other modifications—including m 5 C, m 1 A, m 3 C, m 7 G, and Ψ—play critical roles in RNA folding, stability, translation, and stress responses. Initially, studies focused on each RNA modification individually, but recent evidence has revealed that these modifications often occur together, forming interconnected networks in which each modification can influence others, ultimately determining transcript fate and cellular states. In this review, we synthesize insights across the full spectrum of RNA modifications, highlight combinatorial regulation, and examine technological advances that enable mechanistic dissection and translational exploration. By emphasizing how modifications cooperate rather than act alone, this review aims to shift the field toward a holistic, network-based understanding of epitranscriptomic regulation in human disease. • This review provides a comprehensive, mechanistically integrated overview of major RNA modifications (m 6 A, m 1 A, m 7 G, m 5 C, m 3 C, and pseudouridine) and their coordinated impact on gene expression regulation. • It introduces a unified conceptual framework that connects writers, erasers, and readers with signaling pathways, ncRNA interactions, and disease-specific regulatory hierarchies. • The article shifts the field from a m 6 A-centered perspective to a network-based understanding of the epitranscriptome, emphasizing crosstalk among different RNA modifications. • It summarizes emerging single-cell and nanopore sequencing technologies, explaining how they enable simultaneous detection and functional mapping of multiple RNA marks in real time. • The review highlights translational implications of epitranscriptomic regulation, linking molecular mechanisms to potential diagnostic and therapeutic applications in cancer, neurological, immune, and metabolic disorders.