HOMER3 is a postsynaptic density scaffolding protein that serves dual roles in synaptic signaling and disease pathology. In normal neurological function, HOMER3 binds and cross-links cytoplasmic regions of metabotropic glutamate receptors (GRM1/GRM5) with intracellular calcium release channels (ITPR1), coupling surface receptor activation to intracellular calcium mobilization and maintaining glutamatergic synapse plasticity [UniProt]. Additionally, HOMER3 negatively regulates T cell activation by competing with calcineurin for NFAT binding, thereby inhibiting pro-inflammatory responses. Disease relevance of HOMER3 is substantial. In autoimmune vestibulocerebellar syndromes, HOMER3 serves as a synaptic autoantigen target, with anti-HOMER3 antibodies implicated in cerebellar dysfunction and ataxia 1. Conversely, HOMER3 overexpression promotes malignancy across multiple cancer types: in prostate cancer, HOMER3 activates YAP1 signaling and upregulates CD274 (PD-L1), fostering immunosuppression 2; in glioma, HOMER3 drives proliferation and metastasis through Wnt/β-catenin/EMT pathways 3; in non-small cell lung cancer, HOMER3 enhances mitochondrial metabolism via GABPB1 4; in oral squamous cell carcinoma, HOMER3 promotes progression through TRPV6-mediated calcium influx and chemoresistance 5; and in hepatocellular carcinoma, HOMER3 activates the miR-361/GPNMB axis 6. Notably, HOMER3 and HOMER2 inhibit amyloid-β production by regulating APP processing and trafficking, suggesting neuroprotective potential in Alzheimer's disease 78. These findings identify HOMER3 as a critical determinant in both neuroinflammatory diseases and oncogenic progression.