Thyroid hormone signaling pathway (TH pathway)

The thyroid hormone signaling pathway is a fundamental endocrine system that regulates growth, development, and metabolic homeostasis across nearly all vertebrate tissues (Mullur et al., 2014). It is primarily controlled by the hypothalamic-pituitary-thyroid (HPT) axis, which regulates the production and release of thyroxine (T4) and triiodothyronine (T3) (StatPearls, 2023). Within target cells, T4 is converted to the more active T3 by deiodinase enzymes, and T3 then binds to nuclear thyroid hormone receptors (TRα and TRβ) (NIH, 2023). These receptors function as ligand-dependent transcription factors, binding to thyroid response elements (TREs) in the promoters of target genes to modulate their expression (Mullur et al., 2014). Dysregulation of this pathway is central to the pathogenesis of hypothyroidism, hyperthyroidism, and resistance to thyroid hormone syndromes (StatPearls, 2023). Pharmacological intervention typically involves hormone replacement therapy with synthetic T4 or T3, or the use of antithyroid drugs that inhibit hormone synthesis (StatPearls, 2023). More recently, selective TRβ agonists like resmetirom have been developed to treat metabolic conditions like metabolic dysfunction-associated steatohepatitis (MASH) by leveraging the receptor's role in hepatic lipid metabolism while minimizing systemic side effects (Harrison et al., 2019).

Other names

Hypothalamic-pituitary-thyroid axisHPT axisT3/T4 signalingThyroid hormone signaling

The pathway is modulated by thyroid hormone replacement (agonism of TRα/TRβ), inhibition of thyroid peroxidase (TPO) to reduce hormone synthesis, or selective activation of TRβ to target hepatic metabolism (StatPearls, 2023; Harrison et al., 2019).