The Calcineurin–Nuclear Factor of Activated T Cells Signaling Axis in Hypertrophic Cardiomyopathy: Molecular Insights and Therapeutic Implications

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder characterized by maladaptive myocardial hypertrophy, fibrosis, and an increased risk of arrhythmias and sudden cardiac death. Although HCM arises from mutations in sarcomeric proteins, accumulating evidence indicates that downstream calcium-dependent signaling pathways drive pathological remodeling. Among these, the calcineurin-nuclear factor of activated T cells (NFAT) axis has emerged as a central mediator linking altered calcium handling and mechanical stress to hypertrophic gene transcription. Experimental studies in transgenic animals, human myocardial tissue, and induced pluripotent stem cell-derived cardiomyocytes demonstrate that sustained calcineurin activation promotes NFAT nuclear translocation and reactivation of fetal gene programs characteristic of HCM. Pharmacologic inhibition of calcineurin attenuates pathological hypertrophy in multiple preclinical models, although systemic toxicity and inconsistent efficacy limit clinical translation. Consequently, novel therapeutic strategies, including cardiac-targeted gene therapy, NFAT decoy oligonucleotides, peptide-based inhibitors, and modulation of regulatory signaling nodes, have been developed to achieve pathway-specific suppression with improved safety. Despite challenges related to signaling redundancy, disease heterogeneity, and optimal timing of intervention, selective targeting of calcineurin-NFAT signaling represents a promising disease-modifying approach for HCM, with the potential to shift management beyond symptomatic treatment toward precision-based molecular therapy.