Biological properties of α-actinin-2 and its role and mechanisms in disease development

α-Actinin-2 (encoded by the ACTN2 gene) is a critical cytoskeletal protein predominantly expressed in skeletal and cardiac muscle, where it anchors actin filaments to the sarcomeric Z-disk. While its structural role is well-established, emerging evidence increasingly implicates ACTN2 dysfunction in a spectrum of disorders, including cardiomyopathies, distal myopathies, and neurodegenerative conditions. Despite these established associations, a systematic synthesis of the structure-function relationship of α-Actinin-2 and its pathogenic mechanisms remains lacking. This review comprehensively summarizes the multifaceted roles of α-Actinin-2, ranging from its molecular architecture and cytoskeletal regulation to its involvement in diverse signaling pathways. Furthermore, we establish an analytical framework connecting specific genetic variants to clinical phenotypes, thereby providing theoretical insights to facilitate the identification of diagnostic biomarkers and the development of targeted therapeutic strategies.