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NEXN deficiency leads to dilated cardiomyopathy in human pluripotent stem cell-derived cardiomyocytes

ABSTRACT: Dilated cardiomyopathy (DCM) constitutes a major cause of heart failure, characterized by high mortality rates and a limited availability of effective therapeutic options. A substantial body of evidence indicates that mutations in the Nexilin (NEXN) gene are significant pathogenic contributors to DCM, and we have developed a NEXN-deficient human cardiac myocyte model that faithfully replicated the pathophysiological characteristics of DCM. This model addressed the limitations associated with interspecies physiological differences and was highly suitable for further investigation into the underlying pathogenesis. We demonstrated that NEXN was one of the important components in maintaining the structure and function of cardiomyocyte JMCs, and played a key regulatory role in maintaining the normal excitation-contraction coupling of cardiomyocytes. Meanwhile, NEXN also played a critical role in maintaining the normal energy metabolism of cardiomyocytes, and the loss of its function would lead to DCM. Furthermore, Levo-carnitine and SERCA2a Activator 1 were identified as promising therapeutic agents for the treatment of DCM. Our finding reveals a critical regulatory role of NEXN in JMCs and mitochondria to prevent the development of DCM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282940 | GEO | 2025/06/18

REPOSITORIES: GEO

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