HTR1E (5-hydroxytryptamine receptor 1E) is a G-protein coupled serotonin receptor located on human chromosome 6-q15 1. As a member of the 5-HT1 receptor family, HTR1E functions as a receptor for serotonin and various alkaloids 2. The receptor is coupled to Gi/o G-proteins and mediates inhibitory neurotransmission by suppressing adenylate cyclase activity 3. Upon serotonin binding, HTR1E activates dual signaling cascades: it inhibits cAMP production through Gi-protein coupling and simultaneously activates ERK1/2 phosphorylation via G-protein-dependent mechanisms independent of β-arrestin 34. HTR1E also interacts with neurotrophic factor-α1/carboxypeptidase E to activate β-arrestin/ERK/CREB signaling, promoting neuronal survival during oxidative stress 5. Functionally, HTR1E expression is critical for cell survival; knockdown reduces expression of pro-survival genes including BCL2, cMyc, and Cyclins 3. HTR1E is expressed primarily in brain regions and the pituitary 6, with specific expression in intestinal epithelium during early fetal development 7. Clinically, HTR1E shows emerging significance in cancer biology: decreased HTR1E expression in ovarian cancer correlates with poor outcomes, and HTR1E agonists suppress stress-promoted cancer progression 8. Despite three decades since discovery, HTR1E remains the least-explored serotonin receptor, partly due to its absence in rodent models 2.