HCN3 is a hyperpolarization-activated cation channel that conducts sodium and potassium ions with approximately 3:1 potassium preference 1. It contributes to pacemaker currents in cardiac and neuronal tissues, playing a pivotal role in maintaining excitability and rhythmic burst firing in hypothalamic nuclei [UniProt annotation supported by 22]. HCN3 exhibits distinctive biophysical properties compared to other HCN isoforms: slow activation kinetics and unique cyclic nucleotide sensitivity, with cAMP/cGMP inducing unprecedented negative shifts in activation voltage rather than typical positive shifts 3. Notably, human HCN3 is not modulated by intracellular cAMP, distinguishing it from HCN2 and HCN4 1. Clinically, HCN3 dysfunction associates with multiple disorders. Rare variants (R457H, R661Q) significantly reduce current density and have been identified in epilepsy patients, establishing HCN3 as a novel epilepsy candidate gene 4. HCN3 overexpression promotes hepatocellular carcinoma development in a female-biased manner, correlating with poorer patient prognosis 5. HCN3-deficient mice display impaired contextual information processing with attenuated fear extinction 6. The cryo-EM structure reveals cAMP and lipid binding mechanisms 7, providing molecular foundations for developing therapeutic compounds targeting HCN3 for depression, arrhythmia, and epilepsy.