TACR1 encodes tachykinin receptor 1 (NK1R), a G protein-coupled receptor that binds substance P with the highest affinity, followed by neurokinin A and neurokinin B 12. Ligand binding triggers dual signaling pathways: phospholipase C activation leading to phosphatidylinositol hydrolysis and increased intracellular calcium, and adenylate cyclase activation increasing cyclic AMP levels. In cancer biology, TACR1 plays a paradoxical role in breast cancer metastasis. Neuronal substance P acts on tumor cell TACR1 to induce death in a TACR1-high cancer subpopulation; the resulting extracellular ssRNAs activate TLR7 on neighboring cells to promote metastatic progression 3. The TACR1 antagonist aprepitant suppresses tumor growth and metastasis, suggesting therapeutic potential 3. In inflammation, TACR1 mediates substance P signaling in vascular endothelial cells. During sleep deprivation-exacerbated periodontitis, substance P from trigeminal neurons increases TACR1-dependent vascular permeability and pro-inflammatory immune cell infiltration; TACR1 antagonism or vascular endothelial TACR1 knockdown alleviates these effects 4. Genetic variation in TACR1 influences clinical phenotypes. TACR1 polymorphisms associate with postoperative nausea/vomiting sex differences 5, alcohol dependence and sensitivity to NK1R antagonist treatment 6, and bipolar disorder, ADHD, and alcohol dependence syndrome 7. Notably, rs3771863 associates with reduced sicca syndrome risk in fibromyalgia patients 8.