SMPX encodes a small cytoskeleton-associated protein (86-88 amino acids) preferentially expressed in cardiac and skeletal muscles, as well as in inner ear hair cells 1. The protein localizes to costameres and M bands, playing critical roles in coordinating muscle structural and functional states during growth, adaptation, and repair 2. Mechanistically, SMPX functions in cytoskeletal dynamics and mechanical stress responses, with MUSTN1 stabilizing SMPX to maintain myofiber morphology and promote myogenic differentiation 3. In inner ear mechanosensory cells, SMPX localizes to the cytoplasm and primary cilium of hair cells, where it is essential for proper hair cell differentiation and mechanotransduction activity 4. Loss-of-function mutations cause two clinically distinct phenotypes: X-linked progressive non-syndromic hearing loss through impaired hair cell kinocilia structure and mechanotransduction 5, and late-onset distal myopathy characterized by muscle weakness in hands/feet 6. Recent evidence suggests pathogenic mechanisms involving protein aggregation, stress granule dysregulation, and abnormal Rac1/p38 signaling 7. These findings establish SMPX as a pleiotropic gene with critical roles in both auditory and skeletal muscle homeostasis, expanding beyond its initial classification as a non-syndromic deafness gene.