Small molecules modulate the biomolecular condensates and liquid‒liquid phase separation

Phase separation of biological macromolecules is a ubiquitous cellular mechanism for concentrating and compartmentalizing biochemical reactions. Emerging evidence reveals that biomolecular condensates formed via liquid-liquid phase separation (LLPS) play integral roles in diverse physiological processes, including gene expression and intracellular signaling, enabling rapid and delicate cellular responses. Dysregulation of phase separation is increasingly implicated in the pathogenesis of major diseases, ranging from neurodegenerative disorders and cancers to viral infections and aging. Consequently, deciphering the molecular mechanisms governing LLPS and developing strategies for its pharmacological modulation, particularly via small molecules, represent promising therapeutic targets offering novel approaches for disease intervention. In this review, we provide a concise overview of biomolecular condensates formation and their functions in diseases regulation. Mainly, we catalog commonly employed tool compounds, reported small-molecule modulators of LLPS, and related clinical progress within this rapidly evolving research area. Furthermore, we integrate recent technological breakthroughs in LLPS to envision the future trajectory and therapeutic potential of this field.