TSHR is a G protein-coupled receptor located on chromosome 14 that serves as the primary receptor for thyroid-stimulating hormone (TSH) and thyrostimulin 12. Upon ligand binding, TSHR activates Gs proteins to stimulate adenylate cyclase, generating cyclic AMP (cAMP) and activating protein kinase A (PKA) 34. This signaling cascade phosphorylates downstream targets including thyroid peroxidase and the sodium/iodide symporter, promoting thyroid hormone biosynthesis and secretion 5. Structurally, TSH and activating autoantibodies induce an upright conformation of TSHR's extracellular domain through a conserved ten-residue hinge fragment, whereas inhibitory antibodies prevent this activation 4. TSHR dysfunction has major clinical relevance: autoantibodies activate TSHR as agonists in Graves' disease, the most common cause of hyperthyroidism, causing excessive thyroid hormone secretion and Graves' orbitopathy through IGF-1R crosstalk 67. TSHR gene methylation shows increased rates in papillary thyroid cancer and correlates with adverse clinicopathological features including lymph node metastasis 8. Additionally, TSHR rs179247 polymorphisms associate with increased Graves' disease susceptibility 9, while mutations cause congenital hypothyroidism 10.