GRK5 is a serine/threonine kinase that phosphorylates activated G protein-coupled receptors (GPCRs), initiating β-arrestin-mediated receptor desensitization and internalization 1. Beyond GPCRs, GRK5 phosphorylates diverse substrates including p53, HDAC5, and arrestin-1, regulating apoptosis and myocyte gene expression. GRK5 plays critical roles in cardiac physiology by controlling β1-adrenergic receptor signaling; cardiac-specific GRK5 deletion prevents adrenergic-induced dissociation of the β1AR-SAP97 complex and reduces detrimental CaMKII activation in heart failure 2. Dysregulated GRK5 expression contributes to pathological cardiac hypertrophy and heart failure progression, making it a therapeutic target 3. GRK5 variants are associated with stroke risk across multiple ancestries 4, while GRK5 polymorphisms influence breast cancer susceptibility and tumor characteristics in Chinese populations 5. GRK5 deficiency also causes mild cognitive impairment in aging mice and exacerbates Alzheimer's disease pathology, suggesting GRK5 as a preventive target for cognitive decline 6. Despite pharmacogenetic studies examining GRK5 genotypes with beta-blocker therapy, current evidence is insufficient for clinical recommendations beyond CYP2D6-metoprolol associations 7. Small-molecule GRK5 inhibitors are under development for cardiovascular and neurodegenerative diseases 1.