Cell mechanosensing at focal adhesions: Emerging insights from phase separation

Focal adhesions are central structures that allow cells to sense and respond to extracellular mechanical cues, yet traditional interaction-based models cannot fully explain their efficient protein enrichment, rapid turnover, and strong mechanical sensitivity. Recent studies highlight liquid-liquid phase separation (LLPS) as a novel physicochemical mechanism that reshapes our understanding of focal adhesion organization and function. This review summarizes current mechanisms of focal adhesion-mediated mechanosensing, with a focus on the emerging role of phase separation. Several core focal adhesion proteins, such as talin and paxillin, can form biomolecular condensates whose assembly is regulated by mechanical forces and post-translational modifications. These condensates offer a mechanism for converting mechanical inputs into biochemical signals. We highlight how phase separation contributes to focal adhesion assembly, maturation, cytoskeletal regulation, and dynamic turnover. The concept of LLPS provides a unified framework for understanding focal adhesion behavior and advances our understanding of cellular mechanosensing.