{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThyroid hormone receptor β (THRB) is a ligand‐activated transcription factor that mediates the genomic actions of thyroid hormone. Structural and biochemical studies have shown that specific substitutions and subtle single‐nucleotide changes—including even silent polymorphisms—can alter the receptor’s ligand‐binding pocket and its ability to recruit coactivators or release corepressors. In addition to its classic genomic activities, THRB can also mediate rapid, non‐genomic signals (for example, via PI3K/Akt activation) that influence cell proliferation, survival, and metabolic pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn developmental and homeostatic contexts, THRB plays crucial roles beyond classical thyroid hormone regulation. Proper THRB signaling is essential for postnatal morphogenesis in the auditory system, and alternative ligands (such as 3,5‐diiodothyronine) may selectively activate THRB isoforms to yield tissue‐specific outcomes. Moreover, THRB activity modulates hypoxia‐inducible responses and metabolic adaptations, with genetic variations in its coding region correlating with thyroid parameters, aspects of male sexual function, and even bronchodilator responsiveness. Work in non‐mammalian models further underscores its evolutionary conservation—for instance, in amphibian metamorphosis, where loss of THRB function leads to arrested developmental transitions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTHRB dysregulation has emerged as a common feature in a variety of pathological states, including multiple cancers and developmental disorders. Loss of expression, somatic mutations, or epigenetic silencing of THRB have been documented in thyroid, colorectal, hepatic, renal, and breast carcinomas, implicating this receptor as a tumor suppressor. Mouse models carrying dominant‐negative THRB mutations develop metastatic thyroid cancer, and in human tumors reduced receptor activity correlates with an aggressive phenotype. Furthermore, alterations in THRB can lead to clinical syndromes such as resistance to thyroid hormone and even contribute to disorders of the sensory system (for example, cone photoreceptor dysfunction). Collectively, these findings support the critical role of THRB in regulating gene expression programs that maintain normal cell differentiation and growth while preventing tumorous transformation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "39"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Adhirai Marimuthu, Weijun Feng, Tetsuya Tagami, et al. 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