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Introduction: Energy status can alter thyroid hormone signalling in different tissues. Little is known about the effect of fasting on the local thyroid hormone metabolism under high-fat diet (HFD)-induced obesity. We aimed to investigate the fasting effect on deiodinase type 3 (DIO3) and thyroid hormone receptors (TRs) expression in liver and visceral adipose tissue (VAT) of HFD-induced obese mice. Methods: The 30 male C57BL/6 mice were divided into three groups (n = 10/group): control (CON) group, obese (OB) group, and fasted obese (OBF) group. Materials: In a 14-week study, the expression levels of DIO3 and TRs in the liver and VAT of mice were measured by real-time polymerase chain reaction. Gene expression results were shown as fold changes defined by 2-ΔΔct. Comparison between groups was performed by using one-way-ANOVA or Kruskal-Wallis ANOVA test. Results: In the liver, there was a significantly lower expression of DIO3 and higher expression of TRs in obese fasted mice compared to obese mice. Compared to the lean mice, OBF mice had significantly lower expression of DIO3 and higher expression of TRß. In the VAT, mRNA expression of DIO3 was significantly increased in OBF and OB groups compared to the CON group. There were no significant differences in the mRNA expression of TRs between groups. Conclusion: Our findings suggest that fasting may be more effective in improving thyroid hormone metabolism in the liver rather than the VAT of obese mice.

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Thyroid hormones play a crucial role in numerous physiological processes, including reproduction. Bisphenol S (BPS) is a structural analog of Bisphenol A known for its toxic effects. Interference of this substitute with normal thyroid function has been described. To investigate the effect of thyroid disruption on ovarian development following maternal exposure to BPS, female rats were exposed, daily, to either AT 1-850 (a thyroid hormone receptor antagonist) (10 nmol/rat) or BPS (0.2 mg/kg) during gestation and lactation. The effects on reproductive outcome, offspring development, histological structures, hormone levels, oxidative status, cytoskeleton proteins expression, and oocyte development gene expression were examined. Our results are in favor of offspring ovarian development disruption due to thyroid disturbance in adult pregnant females. During both fetal and postnatal stages, BPS considerably altered the histological structure of the thyroid tissue as well as oocyte and follicular development, which led to premature ovarian failure and stimulation of oocyte atresia, being accompanied with oxidative stress, hypothalamic-pituitary-ovarian axis disorders, and cytoskeletal dynamic disturbance. Crucially, our study underscores that BPS may induce reproductive toxicity by blocking nuclear thyroid hormone receptors, evidenced by the parallelism and the perfect meshing between the data obtained following exposure to AT 1-850 and those after the treatment by this substitute.

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BACKGROUND AND AIMS: Thyroid hormones are important regulators of hepatic lipid homeostasis and whole-body energy expenditure. Recent evidence suggests that euthyroid individuals with metabolic dysfunction-associated steatohepatitis (MASH) develop intrahepatic hypothyroidism that promotes progression of MASH. METHODS: A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases from inception till March 2024, using the following keywords: hypothyroidism and nonalcoholic fatty liver disease; MASLD and thyroid function; intrahepatic hypothyroidism; TRß agonists; and resmetirom. Relevant studies were extracted that described pathogenesis of MASH in the context of thyroid functions. RESULTS: In euthyroid individuals with MASH, there is decreased conversion of prohormone thyroxine (T4) to bioactive tri-iodothyronine (T3) and increased conversion of T4 to inactive metabolite reverse T3 (rT3). Consequently, reduced levels of T3 results in impaired intrahepatic TRß signaling, a state of intrahepatic hypothyroidism, which promotes progression of MASH. Hepatic TRß activation leads to metabolically beneficial effects in the liver including mitochondrial fatty acid uptake and ß-oxidation, mitochondrial biogenesis, increasing surface low-density lipoprotein (LDL) receptor density and lowering of circulatory LDL-cholesterol. In recent years, selective thyroid hormone mimetics that exhibit TRß-selective binding and liver-selective uptake have been designed. Resmetirom, a liver-specific thyromimetic, improves intrahepatic TRß signaling and in clinical trials significantly improved liver inflammation, fibrosis and lipid profile in patients with MASH. CONCLUSIONS: In euthyroid individuals with MASH, development of intrahepatic hypothyroidism results in further progression of the disease. In clinical trials, resmetirom treatment results in a significant improvement in steatosis, inflammation and fibrosis and is the first drug approved by the US Food and Drug Administration (FDA) for the treatment of noncirrhotic MASH with moderate to advanced fibrosis.

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Dihydroxylated polybrominated diphenyl ethers (DiOH-PBDEs) could be the metabolites of PBDEs of some organisms or the natural products of certain marine bacteria and algae. OH-PBDEs may demonstrate binding affinity to thyroid hormone receptors (TRs) and can disrupt the functioning of the systems modulated by TRs. However, the thyroid hormone disruption mechanism of diOH-PBDEs remains elusive due to the absence of diOH-PBDEs standards. This investigation explores the potential disruptive effects of OH/diOH-PBDEs on thyroid hormones via competitive binding and coactivator recruitment with TRα and TRß. At levels of 5000 nM and 25,000 nM, 6-OH-BDE-47 demonstrated significant recruitment of steroid receptor coactivator (SRC), whereas none of the diOH-PBDEs exhibited SRC recruitment within the range of 0.32-25,000 nM. AutoDock CrankPep (ADCP) simulations suggest that the conformation of SRC and TR-ligand complexes, particularly their interaction with Helix 12, rather than binding affinity, plays a pivotal role in ligand agonistic activity. 6,6'-diOH-BDE-47 displayed antagonistic activity towards both TRα and TRß, while the antagonism of 3,5-diOH-BDE-100 for TRα and TRß was concentration-dependent. 3,5-diOH-BDE-17 and 3,5-diOH-BDE-51 exhibited no discernible agonistic or antagonistic activities. Molecular docking analysis revealed that the binding energy of 3,3',5-triiodo-L-thyronine (T3) surpassed that of OH/diOH-PBDEs. 3,5-diOH-BDE-100 exhibited the highest binding energy, whereas 6,6'-diOH-BDE-47 displayed the lowest. These findings suggest that the structural determinants influencing the agonistic and antagonistic activities of halogen phenols may be more intricate than previously proposed, involving factors beyond high-brominated PBDEs or hydroxyl group and bromine substitutions. It is likely that the agonistic or antagonistic propensities of OH/diOH-PBDEs are instigated by protein conformational changes rather than considerations of binding energy.

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Thyroid hormone (TH) signaling plays a major role in mammalian brain development. Data obtained in the past years in animal models have pinpointed GABAergic neurons as a major target of TH signaling during development, which opens up new perspectives to further investigate the mechanisms by which TH affects brain development. The aim of the present review is to gather the available information about the involvement of TH in the maturation of GABAergic neurons. After giving an overview of the kinds of neurological disorders that may arise from disruption of TH signaling during brain development in humans, we will take a historical perspective to show how rodent models of hypothyroidism have gradually pointed to GABAergic neurons as a main target of TH signaling during brain development. The third part of this review underscores the challenges that are encountered when conducting gene expression studies to investigate the molecular mechanisms that are at play downstream of TH receptors during brain development. Unravelling the mechanisms of action of TH in the developing brain should help make progress in the prevention and treatment of several neurological disorders, including autism and epilepsy.

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Oligodendrocytes and their precursors are the cells responsible for developmental myelination and myelin repair during adulthood. Their differentiation and maturation processes are regulated by a complex molecular machinery driven mainly by triiodothyronine (T3), the genomic active form of thyroid hormone, which binds to thyroid hormone receptors (TRs), regulating the expression of target genes. Different molecular tools have been developed to mimic T3 action in an attempt to overcome the myelin repair deficit that underlies various central nervous system pathologies. In this study, we used a well-established in vitro model of neural stem cell-derived oligodendrocyte precursor cells (OPCs) to test the effects of two compounds: the TRß1 ligand IS25 and its pro-drug TG68. We showed that treatment with TG68 induces OPC differentiation/maturation as well as both the natural ligand and the best-known TRß1 synthetic ligand, GC-1. We then described that, unlike T3, TG68 can fully overcome the cytokine-mediated oligodendrocyte differentiation block. In conclusion, we showed the ability of a new synthetic compound to stimulate OPC differentiation and overcome inflammation-mediated pathological conditions. Further studies will clarify whether the compound acts as a pro-drug to produce the TRß1 ligand IS25 or if its action is mediated by secondary mechanisms such as AMPK activation.

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The hypothalamic pituitary thyroid axis is a major regulator of many differentiation processes, including adipose tissue. However, it remains unclear whether and how thyroid hormone (TH) signaling contributes to preadipocyte commitment and differentiation into mature adipocytes. Here, we show a cell-autonomous effect of TH on the transcriptional regulation of zinc finger protein 423 (Zfp423), an early adipogenic determination factor, in murine adipose depots. Mechanistically, binding of the unliganded TH receptor to a negative TH responsive element within the Zfp423 promoter activates transcriptional activity that is reversed upon TH binding. Zfp423 upregulation is associated with increased GFP+ preadipocyte recruitment in stromal vascular fraction isolated from white fat of hypothyroid Zfp423GFP reporter mice. RNA sequencing identified Zfp423-driven gene programs that are modulated in response to TH during adipogenic differentiation. Collectively, we identified Zfp423 as a key molecule that integrates TH signaling into the regulation of adipose tissue plasticity.

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Hypothyroidism in the setting of cancer is a puzzling entity due to the dual role of the thyroid hormones (TH) in cancer - promoting versus inhibitory - and the complexity of the hypothyroidism itself. The present review provides a comprehensive overview of the personalized approach to hypothyroidism in patients with solid nonthyroid cancer, focusing on current challenges, unmet needs and future perspectives. Major electronic databases were searched from January 2011 until March 2022. The milestones of the refinement of such a personalized approach are prompt diagnosis, proper TH replacement and development of interventions and/or pharmaceutical agents to exploit hypothyroidism or, on the contrary, TH replacement as an anticancer strategy. Further elucidation of the dual role of TH in cancer - especially of the interference of TH signaling with the hallmarks of cancer - is anticipated to inform decision-making and optimize patient selection.

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Background: Thyroid hormone (triiodothyronine [T3]) is essential for development and organ metabolism in all vertebrates. T3 has both genomic and nongenomic effects on target cells. While much has been learnt on its genomic effects via T3 receptors (TRs) in vertebrate development, mostly through TR-knockout and TR-knockin studies, little is known about the effects of T3 on gene expression in animals in the absence of TR. We have been studying Xenopus metamorphosis as a model for mammalian postembryonic development, a period around birth when plasma T3 level peaks and many organs/tissues mature into their adult forms. We have recently generated TR double knockout (TRDKO) Xenopus tropicalis animals. This offers an opportunity to compare the effects of T3 on global gene expression in tadpole tissues in the presence or absence of TR. Methods: We analyzed the effects of T3 on gene expression in tadpole tail and intestine by using RNA-seq analysis on wild-type and TRDKO tadpoles with or without T3 treatment. Results: We observed that removing TRs reduced the number of genes regulated by T3 in both organs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that T3 affected distinct biological processes and pathways in wild-type and TRDKO tadpoles. Many GO terms and KEGG pathways that were enriched among genes regulated in wild-type tissues are likely involved in mediating the effects of T3 on metamorphosis, for example, those related to development, stem cells, apoptosis, and cell cycle/cell proliferation. However, such GO terms and pathways were not enriched among T3-regulated genes in TRDKO tadpoles. Instead, in TRDKO tadpoles, GO terms and pathways related to "metabolism" and "immune response" were highly enriched among T3-regulated genes. We further observed strong divergence in the TR-independent nongenomic effects of T3 in the intestine and tail. Conclusions: Our data suggest that T3 has distinct and organ-dependent effects on gene expression in developing tadpoles. The TR-mediated effects are consistent with the metamorphic changes, in agreement with the fact that TR is necessary and sufficient to mediate the effects of T3 on metamorphosis. T3 appears to have a major effect on metabolism and immune response via TR-independent nongenomic processes.

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The hypothalamic-pituitary-thyroid (HPT) axis is crucial in regulating thyroid hormone levels that contribute to the development and homeostasis of the human body. Current literature supports the presence of a local HPT axis equivalent within keratinocytes of the skin, with thyroid hormones playing a potential role in cancer progression. However, this remains to be seen within oral tissue cells. An electronic search of Scopus and PubMed/Medline databases was conducted to identify all original publications that reported data on the production or effects of HPT axis components in normal or malignant cells of the oral cavity. The search identified 221 studies, of which 14 were eligible. Eight studies were retrospective analyses of clinical samples, one study involved both in vivo and in vitro experiments, and the remaining five studies were conducted in vitro using cell lines. The search identified evidence of effects of HPT components on oral cancer cells. However, there were limited data for the production of HPT axis components by oral tissues. We conclude that a possible role of the local HPT axis equivalent in the oral mucosa may not be established at present. The gaps in knowledge identified in this scoping review, particularly regarding the production of HPT components by oral tissues, warrant further investigation.

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We gathered available RNA-seq and ChIP-seq data in a single database to better characterize the target genes of thyroid hormone receptors in several cell types. This database can serve as a resource to analyze the mode of action of thyroid hormone (T3). Additionally, it is an easy-to-use and convenient tool to obtain information on specific genes regarding T3 regulation or to extract large gene lists of interest according to the users' criteria. Overall, this atlas is a unique compilation of recent sequencing data focusing on T3, its receptors, modes of action, targets and roles, which may benefit researchers within the field. A preliminary analysis indicates extensive variations in the repertoire of target genes where transcription is upregulated by chromatin-bound nuclear receptors. Although it has a major influence, chromatin accessibility is not the only parameter that determines the cellular selectivity of the hormonal response.

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Butylated hydroxytoluene (BHT) is a synthetic antioxidant widely used in many industrial sectors. BHT is a well-studied compound for which there are many favorable regulatory decisions. However, a recent opinion by the French Agency for Food, Environmental and Occupational Health and Safety (ANSES) hypothesizes a role for BHT in endocrine disruption (ANSES (2021). This opinion is based on observations in mostly rat studies where changes to thyroid physiology are observed. Enzymatic induction of Cytochrome P450-mediated thyroid hormone catabolism has been proposed as a mechanism for these observations, however, a causal relationship has not been proven. Other evidence proposed in the document includes a read across argument to butylated hydroxyanisole (BHA), another Community Rolling Action Plan (CoRAP)-listed substance with endocrine disruption concerns. We tested the hypothesis that BHT is an endocrine disruptor by using a Next Generation Risk Assessment (NGRA) method. Four different cell lines: A549, HCC1428, HepG2, and MCF7 were treated with BHT and a series of BHT analogs at 5 different concentrations, RNA was isolated from cell extracts and run on the L1000 gene array platform. A toxicogenomics-based assessment was performed by comparing BHT's unique genomic signature to a large external database containing signatures of other compounds (including many known endocrine disruptors) to identify if any endocrine disruption-related modes of action (MoAs) are prevalent among BHT and other compounds with similar genomic signatures. In addition, we performed a toxicogenomics-based structure activity relationship (SAR) assessment of BHT and a series of structurally similar analogs to understand if endocrine disruption is a relevant MoA for chemicals that are considered suitable analogs to BHT using the P&G read across framework (Wu et al., 2010). Neither BHT nor any of its analogs connected to compounds that had endocrine activity for estrogens, androgens, thyroid, or steroidogenesis.

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Development and differentiation of the thyroid gland is directed by expression of specific transcription factors in the thyroid follicular cell which mediates hormone biosynthesis. Membrane transporters are rate-limiting for cellular entry of thyroid hormones (TH) (T4 and T3) into some tissues, with selenocysteine-containing, deiodinase enzymes (DIO1 and DIO2) converting T4 to the biologically active hormone T3. TH regulate expression of target genes via hormone-inducible nuclear receptors (TRα and TRß) to exert their physiological effects. Primary congenital hypothyroidism (CH) due to thyroid dysgenesis may be mediated by defects in thyroid transcription factors or impaired thyroid stimulating hormone receptor function. Dyshormonogenic CH is usually due to mutations in genes mediating thyroidal iodide transport, organification or iodotyrosine synthesis and recycling. Disorders of TH signalling encompass conditions due to defects in membrane TH transporters, impaired hormone metabolism due to deficiency of deiodinases and syndromes of Resistance to thyroid hormone due to pathogenic variants in either TRα or TRß. Here, we review the genetic basis, pathogenesis and clinical features of congenital, dysgenetic or dyshormonogenic hypothyroidism and disorders of TH transport, metabolism and action.

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Hypothyroidism in patients with solid non-thyroid cancer is a tantalizing entity, integrating an intriguing thyroid hormones (THs)-cancer association with the complexity of hypothyroidism itself. The present narrative review provides a comprehensive overview of the clinical relevance of hypothyroidism in solid non-thyroid cancer. Hypothyroidism in patients with solid non-thyroid cancer is reminiscent of hypothyroidism in the general population, yet also poses distinct challenges due to the dual role of THs in cancer: promoting versus inhibitory. Close collaboration between oncologists and endocrinologists will enable the prompt and personalized diagnosis and treatment of hypothyroidism in patients with solid non-thyroid cancer. Clinical data indicate that hypothyroidism is a predictor of a decreased or increased risk of solid non-thyroid cancer and is a prognostic factor of favorable or unfavorable prognosis in solid non-thyroid cancer. However, the impact of hypothyroidism with respect to the risk and/or prognosis of solid non-thyroid cancer is not a consistent finding. To harness hypothyroidism, or THs replacement, as a personalized anticancer strategy for solid non-thyroid cancer, four prerequisites need to be fulfilled, namely: (i) deciphering the dual THs actions in cancer; (ii) identifying interventions in THs status and developing agents that block tumor-promoting THs actions and/or mimic anticancer THs actions; (iii) appropriate patient selection; and (iv) counteracting current methodological limitations.

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Skeletal muscle is a key energy-regulating organ, skilled in rapidly boosting the rate of energy production and substrate consumption following increased workload demand. The alteration of skeletal muscle metabolism is directly associated with numerous pathologies and disorders. Thyroid hormones (THs) and their receptors (TRs, namely, TRα and TRß) exert pleiotropic functions in almost all cells and tissues. Skeletal muscle is a major THs-target tissue and alterations of THs levels have multiple influences on the latter. However, the biological role of THs and TRs in orchestrating metabolic pathways in skeletal muscle has only recently started to be addressed. The purpose of this paper is to investigate the muscle metabolic response to TRs abrogation, by using two different mouse models of global TRα- and TRßKO. In line with the clinical features of resistance to THs syndromes in humans, characterized by THRs gene mutations, both animal models of TRs deficiency exhibit developmental delay and mitochondrial dysfunctions. Moreover, using transcriptomic and metabolomic approaches, we found that the TRs-THs complex regulates the Fatty Acids (FAs)-binding protein GOT2, affecting FAs oxidation and transport in skeletal muscle. In conclusion, these results underline a new metabolic role of THs in governing muscle lipids distribution and metabolism.

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Bromoacetamide (BAcAm) is a nitrogenous disinfection by-product. We previously found that BAcAm induced developmental toxicity in zebrafish embryos, but the underlying mechanisms remain to be elucidated. Since thyroid hormones (THs) homeostasis is crucial to development, we hypothesized that disruption of THs homeostasis may play a role in the developmental toxicity of BAcAm. In this study, we found BAcAm exposure significantly increased mortality and malformation rate, decreased hatching rate and body length, inhibited the locomotor capacity in zebrafish embryos. BAcAm elevated TSH, T3 and T4 levels, down-regulated T3/T4 ratios, and up-regulated mRNA expression changes of THs related genes (trh, tsh, tg, nis, tpo, dio1, dio2, ugt1ab，klf9 and rho), but down-regulated mRNA expression changes of TH receptors (tr α and tr ß). Up-regulated tr α and tr ß mRNAs by rescue treatment confirmed that both tr α and tr ß were involved in the developmental toxicity of BAcAm. In conclusion, our study indicates disruption of THs homeostasis via the thyroid hormone receptors was responsible for the developmental toxicity of BAcAm.

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Dechloranes are a group of halogenated flame retardants with a basic bicyclo[2.2.1]heptene, including Dechlorane Plus (DP), Dechlorane 602 (Dec 602), Dechlorane 603 (Dec 603) and Dechlorane 604 (Dec 604). A few epidemiological investigations and animal experiments have shown that DP exhibited thyroid-interfering effects. In the present study, we investigated whether DP and three other dechloranes could interfere the thyroid function through thyroid hormone receptors (TRs, TRα and TRß) signaling pathways. The binding affinities of the four dechloranes to the two TRs were determined by fluorescence competitive binding assay. It was found that all the four dechloranes could bind with the two TRs. The relative potency (RP) values ranged from nd (not detectable) to 0.0667. Between the two TRs, dechloranes were more inclined to bind with TRß, which implies that the thyroid interference effect of dechloranes may have selectivity in different tissues and organs. TRs-mediated luciferase reporter gene assay and T-screen assay showed that all the four dechloranes exhibited antagonistic activity to TRs in the cells. Taken together, our results demonstrated that dechloranes might interfere with thyroid function by binding with TRs and acting as TR antagonists. The health risk of highly exposed human populations should be of serious concern because of the high hazard quotient calculated from our cell assay results.

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Background Rheumatoid Arthritis (RA) patients show a higher risk of heart failure. The present study investigated possible causes of cardiac dysfunction related to thyroid hormone (TH) signaling in a RA mouse model. Methods A TNF-driven mouse model of RA[TghuTNF (Tg197)] was used. Cardiac function was evaluated by echocardiography. SERCA2a and phospholamban protein levels in left ventricle (LV) tissue, thyroid hormone levels in serum, TH receptors in LV and TH-related kinase signaling pathways were measured. T3 hormone was administered in female Tg197 mice. Results We show LV and atrial dilatation with systolic dysfunction in Tg197 animals, accompanied by downregulated SERCA2a. We suggest an interaction of pro-inflammatory and thyroid hormone signaling indicated by increased p38 MAPK and downregulation of TRß1 receptor in Tg197 hearts. Interestingly, female Tg197 mice showed a worse cardiac phenotype related to reduced T3 levels and Akt activation. T3 supplementation increased Akt activation, restored SERCA2a expression and improved cardiac function in female Tg197 mice. Conclusions TNF overexpression of Tg197 mice results in cardiac dysfunction via p38 MAPK activation and downregulation of TRß1. Gender-specific reduction in T3 levels could cause the worse cardiac phenotype observed in female mice, while T3 administration improves cardiac function and calcium handling via modified Akt activation.

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A pivotal role of thyroid hormones and their nuclear receptors in intestinal development and homeostasis have been described, whereas their involvement in intestinal carcinogenesis is still controversial. In this perspective article we briefly summarize the recent advances in this field and present new data regarding their functional interaction with one of the most important signaling pathway, such as WNT, regulating intestinal development and carcinogenesis. These complex interactions unveil new concepts and will surely be of importance for translational research.

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Dysregulation of genes perpetuates cancer progression. During carcinogenesis, cancer cells acquire dependency of aberrant transcriptional programs (known as "transcription addiction") to meet the high demands for uncontrolled proliferation. The needs for particular transcription programs for cancer growth could be cancer-type-selective. The dependencies of certain transcription regulators could be exploited for therapeutic benefits. Anaplastic thyroid cancer (ATC) is an extremely aggressive human cancer for which new treatment modalities are urgently needed. Its resistance to conventional treatments and the lack of therapeutic options for improving survival might have been attributed to extensive genetic heterogeneity due to subsequent evolving genetic alterations and clonal selections during carcinogenesis. Despite this genetic complexity, mounting evidence has revealed a characteristic transcriptional addiction of ATC cells resulting in evolving diverse oncogenic signaling for cancer cell survival. The transcriptional addiction has presented a huge challenge for effective targeting as shown by the failure of previous targeted therapies. However, an emerging notion is that many different oncogenic signaling pathways activated by multiple upstream driver mutations might ultimately converge on the transcriptional responses, which would provide an opportunity to target transcriptional regulators for treatment of ATC. Here, we review the current understanding of how genetic alterations in cancer distorted the transcription program, leading to acquisition of transcriptional addiction. We also highlight recent findings from studies aiming to exploit the opportunity for targeting transcription regulators as potential therapeutics for ATC.