Modulating Thyroid Hormones: Advances in TRβ-Selective Ligands, Enzyme Inhibitors, and Deiodinase Mimetics for Endocrine Regulation

Thyroid hormones (THs) are critical regulators of metabolic homeostasis, influencing a wide array of physiological processes such as protein synthesis, lipid metabolism, neural development, skeletal maturation, and cardiovascular and renal functions. This review provides a comprehensive overview of thyroid hormone biosynthesis, activation, and the molecular mechanisms underlying their action via thyroid hormone receptors (TRs), with an emphasis on the TRβ subtype.We delve into the therapeutic landscape of thyroid hormone analogues and emerging drug candidates—specifically, TRβ-selective ligands and enzyme inhibitors—that target thyroid peroxidase and iodothyronine deiodinases for managing thyroid-related disorders. Special focus is given to the recent advancements in the design and function of small-molecule deiodinase mimetics, which offer promising avenues for precisely modulating thyroid hormone activity and levels in pathological conditions. This review aims to bridge basic endocrine science with translational pharmaceutical approaches, offering insights into novel therapeutic strategies and future directions in the management of thyroid dysfunctions.