Decoding physical environment's role in protein phase transition

Phase transitions, as fundamental phenomena in physical sciences, are well-studied and a full theoretical framework has been established. The research has recently expanded into biological sciences after the milestone discovery of liquid-liquid phase separation (LLPS), and the latest studies are focusing not only LLPS but also liquid-solid phase transition (LSPT). These phase transitions are important fundamental biological processes such as formation of membraneless organelles, and pathogenesis of diseases such as neurodegenerative diseases, type 2 diabetes, and amyloidogenic disorders. These findings provide unprecedented perspectives for deciphering the physicochemical principles underlying living systems and associated disease pathogenesis. In this review we systematically analyze the hierarchical progression of phase transition pathways, delineating how physical factors (e.g., temperature, magnetic field, electric field, etc.) govern transition kinetics and final state selection. The methodological section provides a comprehensive review of experimental techniques applicable in studying phase transitions in biological systems. The elucidation of biological phase transitions is fundamentally important in that it not only provides a novel paradigm for understanding spatiotemporal regulation of cellular organization, but also provides mechanistic insights for developing therapeutic strategies targeting pathological phase transitions. Notably, the identification of physical modulation mechanisms can help to develop non-pharmacological intervention strategies, potentially revolutionizing treatment approaches for protein-misfolding disorders through precisely controlled phase manipulation.