JPH3 (junctophilin 3) is a brain-specific structural protein that forms junctional membrane complexes linking the plasma membrane to the endoplasmic reticulum, facilitating calcium signaling in neurons 1. JPH3 contains six MORN motifs and a transmembrane domain anchoring it to the ER membrane, enabling organized subcellular junctions critical for neuronal function 1. The primary pathogenic mechanism involves CTG trinucleotide repeat expansion in JPH3, causing Huntington disease-like 2 (HDL2), a rare genetic disorder predominantly affecting individuals of African ancestry 2. HDL2 presents with motor, cognitive, and psychiatric features closely resembling Huntington disease, with similar striatal atrophy patterns, though pathogenesis mechanisms remain incompletely understood 2. Beyond neurodegeneration, JPH3 functions as a tumor suppressor in digestive cancers. In hepatocellular and colorectal carcinomas, JPH3 expression is silenced through promoter CpG methylation, associating with poor patient outcomes 34. Restoration of JPH3 expression inhibits cancer cell proliferation, invasion, and migration while promoting mitochondrial-mediated apoptosis through elevated cytosolic calcium and endoplasmic reticulum stress responses 4. Additionally, JPH3 was identified as a potential biomarker for mild cognitive impairment conversion to Alzheimer's disease 5. These findings establish JPH3 as multifunctional—essential for neuronal calcium homeostasis and synaptic function while suppressing tumorigenesis through apoptotic pathways.