RNA Modifications in Health and Disease

Abstract

RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine, and pseudouridine, serve as pivotal regulators of gene expression with significant implications for human health and disease. These dynamic modifications influence RNA stability, splicing, translation, and interactions, thereby orchestrating critical biological processes such as embryonic development, immune response, and cellular homeostasis. Dysregulation of RNA modifications is closely associated with a variety of pathologies. This review systematically synthesizes recent advances in understanding how dynamic RNA modifications orchestrate health and disease. We critically review the m6A modifications, the most abundant RNA methylation, its association with diseases, and regulations by post translation. We evaluate three interconnected themes: disease mechanisms, where dysregulated m6A drives oncogenesis (e.g., METTL3-mediated hypermethylation in breast cancer) and contributes to neuropsychiatric/cardiovascular disorders; homeostatic functions, spanning embryogenesis (maternal-to-zygotic transition), tissue regeneration (YTHDF1 in muscle), and immune regulation; therapeutic frontiers, including enzyme-targeting strategies (FTO inhibitors, METTL3 stabilizers) and diagnostic approaches. Our analysis reveals that context-dependent RNA modification networks operate as biological "switches" whose dysregulation creates pathogenic cascades. We further propose a novel framework for targeting these networks using multiomics integration. This review establishes RNA modifications as central targets for precision medicine, while highlighting critical challenges in clinical translation that demand interdisciplinary collaboration.

Keywords: PTMs; RNA modifications; cancer; cardiovascular health; m6A methylation; neurodegenerative diseases.

FIGURE 1

Several common RNAs modifications. Essential RNA chemical marks: m6A (stability/translation), m5C (RNA structure), Ψ (translational fidelity), m1A (RNA protection). Writer/eraser/reader activities shown via color‐coded symbols (red/blue/green). Collectively regulate gene expression outcomes.

FIGURE 2

PTMs in RNA methylation. Phosphorylation (METTL3↑/FTO↓), acetylation (ALKBH5 stability), ubiquitination (WTAP degradation). Collectively tune methylation flux via signal‐responsive control.

FIGURE 3

Posttranslational modifications associated with METTL3. Stabilization: ERK phosphorylation, PIN1 isomerization, USP5 deubiquitination. Inhibition: SUMOylation, lactylation (↓m6A activity, ↑immunosuppression). Degradation: PLA4 ubiquitination (↓TAB3). Localization: TNFα/CDK9 blocks nuclear entry. Outcomes span cardiac, cancer, immune and metabolic diseases.

FIGURE 4

Posttranslational modifications associated with IGF2BP1 and IGF2BP2. This figure illustrates the posttranslational modifications (PTMs) occurring on IGF2BP1 and IGF2BP2 proteins, including phosphorylation, ubiquitination, and SUMOylation, which regulate target molecule activity.

FIGURE 5

Posttranslational modifications associated with YTHDF2. This figure illustrates the posttranslational modifications (PTMs) occurring on YTHDF2 proteins, including phosphorylation, ubiquitination, and SUMOylation, which regulate target molecule activity.

FIGURE 6

Dual roles of m6A readers in cancer inhibition and promotion via oncogene regulation. Blue: Promote oncogenes in tumor subtypes. Red: Inhibit tumor suppressors. Dashed arrows show cancer‐relevant pathways. Outcomes are microenvironment dependent.