Unraveling Complex MicroRNA Signaling Pathways with Activity‐Based Protein Profiling to Guide Therapeutic Discovery**

Abstract

AbstractmicroRNAs (miRNAs) are important cell factors that can play essential roles, such as regulating transcription factors in embryonic development. Traditionally, microarrays or high‐throughput sequencing of crosslinked protein‐RNA complexes have been applied to deduce direct targets, but these techniques fail to account for biomolecular interactions with functional consequences. Activity‐based protein profiling (ABPP) represents a promising alternative to conventional methods and was applied to the discovery of functional targets of human miRNAs. ABPP identified downregulation of MGLL and LIPC, in response to miR‐185 and miR‐27b, respectively. Hepatitis C virus (HCV) infection was found to be modulated by these indirect downstream effectors. These findings highlight the importance of identifying functional targets in developing novel ways to mimic or inhibit miRNA pathways. This review will focus on miRNA regulation and how ABPP can be used to study these pathways.