HTR1D is a G-protein coupled receptor for serotonin (5-hydroxytryptamine) that functions as an inhibitory neurotransmitter receptor 1234. The receptor binds serotonin and ergot alkaloid derivatives, triggering conformational changes that activate Gi/o G-proteins and inhibit adenylate cyclase activity 14. HTR1D regulates serotonin release in the brain and may modulate release of other neurotransmitters and vascular tone 56. Beyond its classical neurotransmitter role, HTR1D has emerged as a significant player in multiple pathological conditions. In chr1 pain-depression comorbidity, HTR1D in paraventricular thalamic engram neurons represents a potential therapeutic target 7. HTR1D regulates the PI3K/Akt signaling pathway to promote hepatocellular carcinoma proliferation, migration, and sorafenib resistance, with high expression correlating with poor prognosis 8. Similarly, in glioblastoma, HTR1D overexpression enhances proliferation and temozolomide resistance via PI3K/Akt modulation; HTR1D knockdown sensitizes cells to chemotherapy 9. In colorectal cancer, bacterial metabolite N-methylserotonin inhibits cancer progression through HTR1D-mediated suppression of the cAMP-PKA-NF-κB pathway 10. Genetic polymorphisms in HTR1D associate with anorexia nervosa susceptibility 11. Pan-cancer analysis confirms HTR1D's prognostic relevance across multiple malignancies 12.