JPH2 (junctophilin-2) is a multifunctional cardiac protein with dual roles in excitation-contraction coupling and stress-responsive transcriptional regulation. At the membrane, JPH2 maintains calcium homeostasis by regulating store-operated calcium entry through interaction with STIM1, essential for proper cardiac contractility and fibroblast activation 1. Under cardiac stress, calpain-2 cleaves JPH2 at residues 479-486, releasing a C-terminal peptide that translocates to the nucleus where it functions as a transcription repressor, competing with MEF2 transcription factors to suppress pathological genes involved in hypertrophy, inflammation, and fibrosis 2. This protective stress response attenuates cardiac remodeling following myocardial infarction. Clinically, JPH2 variants associate with both hypertrophic and dilated cardiomyopathy, with inheritance patterns correlating phenotype severity: autosomal recessive loss-of-function variants cause severe, early-onset dilated cardiomyopathy, while autosomal dominant missense variants produce heterogeneous presentations including hypertrophic cardiomyopathy and arrhythmias 3. JPH2 holds moderate evidence status for both cardiomyopathy associations 4 5, and incidental JPH2 variants show significant likelihood of DCM pathogenicity in clinical exome sequencing 6. Mutations in calcium signaling genes including JPH2 constitute a convergent pathway in severe childhood cardiomyopathies 7.