Liquid-liquid phase separation: A new pivot in the study of bone homeostasis

Liquid-liquid phase separation (LLPS) is a key mechanism through which biomacromolecules undergo a phase transition to form dynamic membraneless condensates, playing fundamental roles in critical biological processes such as transcriptional regulation, signal transduction, and cell fate determination. Recent studies have demonstrated an important role of LLPS in the regulation of skeletal homeostasis, in which it spatially organizes signaling complexes and transcriptional regulators to precisely coordinate the balance between osteogenic and osteoclast differentiation. This review systematically summarizes the physiological roles of LLPS, with a focus on elucidating the molecular mechanisms and key proteins involved in skeletal homeostasis. Furthermore, it explores the translational potential of LLPS in the development of therapeutic strategies for skeletal disorders and the design of osteoinductive biomaterials. By providing a comprehensive perspective on the LLPS-mediated regulatory network in bone biology, this review aims to offer systematic insights and a theoretical foundation for LLPS-based precision interventions in skeletal diseases.