TMEM64 is a transmembrane protein with critical roles in bone homeostasis and disease pathogenesis. In bone metabolism, TMEM64 positively regulates osteoclast differentiation by modulating TNFSF11-induced calcium signaling through interaction with SERCA2, facilitating cytosolic Ca2+ spiking, NFATC1 activation, and mitochondrial ROS generation 1. Conversely, TMEM64 negatively regulates osteoblast differentiation while promoting adipocyte differentiation by suppressing Wnt/β-catenin signaling and β-catenin nuclear translocation in mesenchymal stem cells, thereby tilting lineage commitment toward adipogenesis 12. This reciprocal regulation is relevant to age-related osteoporosis, where elevated TMEM64 favors bone loss and marrow adiposity. Beyond bone, TMEM64 shows oncogenic functions in hepatocellular carcinoma and glioma, where elevated expression correlates with poor prognosis and promotes tumor cell proliferation, migration, and invasion through Wnt/β-catenin pathway activation 34. Additionally, TMEM64 was identified as a pan-coronavirus host factor requirement for SARS-CoV-2 and seasonal coronavirus infection 5. Emerging evidence suggests TMEM64 involvement in developmental language disorder through altered DNA methylation of Wnt pathway regulators 6, highlighting its pleiotropic roles in human disease.