Regulation of RNA-binding proteins by small biomolecules

RNA-binding proteins (RBPs) are essential for post-transcriptional gene regulation, including for RNA modification such as N⁶-methyladenosine (m⁶A), splicing, polyadenylation, localization, translation and decay. Dysregulation of RBPs has been causally linked to a wide array of human diseases, including cancer, neurodegenerative diseases, metabolic disorders and tissue differentiation abnormalities. Although RBPs have traditionally been studied through their RNA, protein and post-translational interactions, growing evidence shows that small biomolecules (SBMs) such as sugars, nucleotides, metabolites such as S-adenosylmethionine (SAM) and NAD(P)H, and drugs can directly bind RBPs and modulate their structure, localization and RNA-binding activity. These context-dependent and concentration-dependent interactions link RBP regulation to cellular metabolism and are a key focus of current research. In this Review, we discuss the expanding landscape of SBM-binding RBPs and the functions of these RBPs in condensate formation, RNA localization, processing and translation. We highlight the molecular principles that underlie these interactions and their functional relevance to human diseases. We also examine recent advances in the identification of SBM-RBP interactions and the innovative methodologies that are driving discoveries in this rapidly advancing field. Together, these insights underscore the potential of SBMs to modulate RBPs and inform novel therapeutic strategies.