MiRNA Stability and Degradation: Dynamic Regulators of Cellular Regulatory Networks

ABSTRACT MicroRNAs (miRNAs) are pivotal post‐transcriptional regulators of gene networks in development and disease, with their functional output critically dependent on dynamic turnover. Dysregulation of miRNA turnover disrupts signaling fidelity and contributes to pathologies such as cancer and infection. This review synthesizes recent advances in understanding miRNA turnover, focusing on key degradation pathways—including ZSWIM8‐mediated target‐directed miRNA decay (TDMD), TUT4/7‐DIS3L2‐driven uridylation, and nuclease cleavage—and how they integrate with stability factors such as AGO association, terminal modifications, and sequence features to orchestrate global miRNA abundance and health status. From these insights, critical unresolved questions are delineated, such as identifying nucleases responsible for degrading TDMD‐liberated miRNAs and elucidating compartment‐specific degradation mechanisms in physiological contexts like the gut lumen and circulation. Addressing these questions will facilitate innovative strategies for targeting miRNA stability within precision medicine. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action