The RNA structural code: orchestrating gene expression and enabling precision therapies.

Abstract

Following transcription, RNA undergoes hierarchical folding mediated by base pairing and long-range interactions, forming diverse dynamic structures such as local helices, loops, bulges, pseudoknots, G-quadruplexes, riboswitches, and higher-order conformations. These structures function as molecular switches that are recognized by RNA-binding proteins and regulatory factors, thereby precisely controlling the spatiotemporal dynamics of posttranscriptional gene expression. Emerging evidence indicates that aberrant RNA structural dynamics are closely associated with diverse human diseases. RNA-targeted therapeutic strategies, characterized by high specificity, programmability, and broad potential, have emerged as a promising next-generation therapeutic modality beyond conventional small-molecule and antibody-based therapies. Although current RNA-targeted approaches have focused primarily on gene silencing, strategies for enhancing endogenous gene expression are increasingly demonstrating substantial translational potential. In this review, we systematically summarize posttranscriptional gene regulation mechanisms mediated by RNA structural diversity, with a particular emphasis on the roles of RNA structures in alternative splicing, RNA localization and transport, translation, and RNA degradation. We further discuss recent advances, current challenges, and emerging clinical prospects of RNA-targeted therapeutic strategies in human diseases. Overall, this review provides a comprehensive overview of RNA structure‒function relationships and highlights their implications for precision medicine and the development of next-generation RNA-based therapeutics.