MACF1 condensates serve as molecular rheostats translating mechanical stress into bone adaptation

Bone dynamically maintains homeostasis through mechanotransduction, a process essential for skeletal integrity and frequently disrupted in disease. Yet how bone cells decode mechanical cues into adaptive responses remains poorly understood. Here, we identify MACF1, a cytoskeletal crosslinker and core component of stress granules (SGs), as a mechanosensitive scaffold that undergoes phase separation via its intrinsically disordered region 2 (IDR2). In response to distinct mechanical cues, IDR2-driven condensation promotes the recruitment of PIEZO1, paxillin (PXN), and β-catenin (CTNNB1) into SGs, buffering these signaling molecules from ubiquitination-dependent degradation and sustaining osteogenic fidelity. Moreover, we identify an arginine-mutated IDR2 variant that separates protein interactions from condensate formation, revealing IDR2-driven phase separation as a requirement for MACF1-mediated SG assembly and mechanosensitive protein recruitment. Functionally, bone-targeted delivery of MACF1-IDR2 alleviates mechanical unloading-induced bone loss in male mice. These findings reveal a liquid-liquid phase separation (LLPS)-mediated mechanism linking mechanical force sensing and transduction to bone adaptation. Together, these findings support a model in which MACF1 condensates act as molecular rheostats that coordinate mechano-responsive cargo sorting under stress and contribute to skeletal homeostasis. The authors show that mechanosensitive phase separation of MACF1 promotes stress granule formation and mechanosensitive protein recruitment, limiting their ubiquitin-mediated degradation. This supports bone mechanotransduction and homeostasis.