Perra, Andrea

Plateroti, Michelina

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Editorial: Targeting Thyroid Hormone-Dependent Pathways in Proliferative and Degenerative Disorders

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EDITORIALpublished: 08 June 2022doi: 10.3389/fmed.2022.944769Frontiers in Medicine | www.frontiersin.org 1 June 2022 | Volume 9 | Article 944769Edited and reviewed by:Victoria Bunik,Lomonosov Moscow StateUniversity, Russia*Correspondence:Andrea Perraandrea.perra@unica.itSpecialty section:This article was submitted toTranslational Medicine,a section of the journalFrontiers in MedicineReceived: 15 May 2022Accepted: 26 May 2022Published: 08 June 2022Citation:Perra A and Plateroti M (2022)Editorial: Targeting ThyroidHormone-Dependent Pathways inProliferative and DegenerativeDisorders. Front. Med. 9:944769.doi: 10.3389/fmed.2022.944769Editorial: Targeting ThyroidHormone-Dependent Pathways inProliferative and DegenerativeDisordersAndrea Perra 1* and Michelina Plateroti 21Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy,2Université de Strasbourg, Inserm, IRFAC/UMR-S1113, FMTS, Strasbourg, FranceKeywords: thyroid hormones, cell proliferation, T3 analogs, neurological disorders, liver cancerEditorial on the Research TopicTargeting Thyroid Hormone-Dependent Pathways in Proliferative andDegenerative DisordersThyroid hormones (THs) are involved in the control of numerous cellular functions essential forproliferation, differentiation, and metabolism. Alterations of the molecular pathways controlledby THs have been recognized at the basis of numerous human pathologies, including metabolicdiseases, tumors, and some neurodegenerative diseases. The possibility to treat these diseasesby modulating the THs/thyroid hormone receptors (THs/THRs) axis is intriguing, in particularfor pathologies for which, to date, no effective therapy exists. This is the case of hepatocellularcarcinoma (HCC), the most frequent primary liver cancer (1).To ameliorate the outcome of HCC, researchers recently focused their efforts on the possibilityto target new molecular pathways involved in both cell proliferation, differentiation, metabolism,and cyto-protection. Deregulation of the THs/THRs axis has recently been characterized in humanHCC and represents an early event in experimentally-induced liver carcinogenesis in rodents(2). Furthermore, intracellular hypothyroidism has been associated with non-alcoholic fatty liverdisease (NAFLD), that in the next few years will become the main risk factor for chronic andneoplastic liver disease (3). In animal models of both chemically-induced and NAFLD-relatedHCC, the reactivation of the THs/THRs pathway by the administration of high doses oftriiodothyronine (T3) led to the regression of the neoplastic lesions. It had been postulated that T3was able to induce a differentiation program associated with a metabolic rewiring from glycolysisto oxidative phosphorylation (OXPHOS) (4). Together with its anti-tumorigenic potential, T3 hasalso been shown to reduce serum lipids (5) and amelioration of liver fibrosis (6). The possiblemechanisms by which THs balance and THs/THRs activation influence the hepatocarcinogenicprocess and the potential utility of THs and their analogs for the treatment of HCC has beenin-depth reviewed by Lin et al. In their review, Lin and colleagues, describe the major molecularpathways modulated by THs, starting from those controlling proliferation and differentiation.Surprisingly enough, despite its pro-mitogenic effects on normal hepatocytes, T3 demonstratesanti-tumoral effects mediated both by nuclear receptors and cell membrane receptors. Indeed,THs mediate both non-genomic actions through their interaction with the cell surface receptorintegrin αvβ3, and genomic actions by modulating the transcriptional activity of nuclear THRs,which are ligand-dependent transcription factors. Moreover, THRs regulate cell proliferationand metabolism also directly regulating cytoplasmic signaling pathways. TH-regulated pathwayshave been described to be altered not only in human HCC biopsies, but also in preneoplastichepatic lesions obtained from experimental animal models, clearly indicating their importancePerra and Plateroti Editorial: Targeting Thyroid Hormone Pathwaysin hepatocarcinogenesis. The in vivo and in vitro demonstrationof the antitumoral effects of T3 prompted the scientists to designand synthetize T3-analogs, selective for the THRβ isoform,devoid of the cardiovascular side-effects that limited its use.Indeed, high doses of T3 required to induce the anti-steatotic and anti-tumoral effect, also cause severe systemichyperthyroidism, a life-threatening condition. Since most of theharmful effects of T3, directed toward cardiovascular system, aremediated by the alpha-isoform of THRs (THRα), several newT3 analogs selective for the beta isoform of THRβ have beensynthesized. Even if some of them entered clinical trials, they havebeen terminated because of the induction of adverse effects orbecause they failed to meet the clinical end points. Among thesecompounds, the first THRβ selective agonist demonstrating invivo anti-tumoral effects on liver lesions was Sobetirome (GC-1) (7), a drug originally designed to treat hypercholesterolemiaandmixed dyslipidemias. In vivo effects of GC-1 on both NAFLDand liver carcinogenesis led to the synthesis of other GC-1-basedmore liver-selective compounds. A new halogen-free THRβselective molecule (TG68), derived from GC-1, demonstratedan anti-steatogenic activity in vitro and in vivo, in mice fedhigh fat diet (HFD) in the absence of systemic side effects(8). Furthermore, the administration of another new THRβselective compound, Resmetirom, to patients with non-alcoholicsteatohepatitis (NASH) led to a significant reduction in hepaticfat content (9).The interest of clinicians and researchers for the developmentof novel selective analogs of T3 goes beyond their potentialanti-tumoral actions on HCCs. In fact, TH/THRs pathway isalso involved in several common human pathologies, such asdyslipidemias, metabolic, cardiovascular and neurodegenerativediseases. The correlation between THs and serum lipidsconcentration has been established long time ago. Recently,Wu et al. demonstrated an intriguing, although unexpected,association between the diagnosis of hyperthyroidism andabnormal blood lipids profile. In particular, the authors studiedthe correlation between THs levels, lipids concentration andanti-thyroid drugs (ATDs) in more than 13,000 hyperthyroidpatients (in 13,667 patients). Their observations suggestedthat the abnormality in blood lipids was induced by thetreatment of the anti-thyroid drugs 6-n-propyl-2-thiouracil(PTU) and methimazole (MMI). Moreover, the studysuggested that hyperthyroid patients without hyperlipidemiaundergoing standard treatment with anti-thyroid drugs showedsignificantly higher risk of developing hyperlipidemia duringthe follow-up.Even more complex results were obtained by linking THsand cognitive performance. Indeed, whereas T4 levels positivelycorrelate with better general cognition, in patients with mildcognitive impairment T3 levels inversely correlate cognitiveperformance. Starting from the evidence that subjects carryingthe ε4 variant allele of the apolipoprotein E have an increasedrisk to develop mild cognitive impairment or dementia, Leeet al. investigated whether there was a correlation between thepresence of this allele and THs levels. The findings of thisstudy were really fascinating, as the authors demonstrated thathigher levels of T3 could be protective in subjects with mildcognitive impairment carrying the ε4 allele. These results suggestthat T3 supplementation could have a potential therapeutic andpreventive in cognitive deterioration and dementia in APOEε4 carriers. THs supplementation have been proposed also forother neuropsychological diseases, such as maniac and depressedphases of mood disorders and for neurodegenerative diseasessuch as multiple sclerosis (10). As discussed in the reviewby Saponaro et al., there is currently a clear evidence thatmodulation of THs/THRs pathways could represent an effectivestrategy for the treatment of metabolic and neurologic diseases.These findings have further increased the efforts applied in thedevelopment of TH analogs capable of uncoupling beneficialactions on liver and central nervous system from deleteriouseffects on the heart, muscle and bone. In the last decades, severalAryloxyPhenyl based thyromimetics and Diphenylmethanebased THRβ-selective agonists have been developed. Some ofthese molecules, like Sobetirome and its central nervous systemselective prodrug Sob-AM2, demonstrated encouraging resultson brain and spinal cord re-myelination.Despite these encouraging new data, a more completeknowledge of the mechanisms through which THs and theiranalogs modulate cell functions will be fundamental, to designnew therapeutic strategies for the treatment and preventionof some of the most common human diseases. In particular,the development of molecules that selectively activate specificTHR isoforms has opened up the possibility of dissectingproliferative, metabolic, neuroprotective and antineoplasticeffects, allowing, in the coming years, the developmentof new targeted therapies for regenerative medicine andcardiometabolic, neurodegenerative, and neoplastic pathologies.AUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct, and intellectualcontribution to the work and approved it for publication.REFERENCES1. Roddy H, Meyer T, Roddie C. Novel cellular therapies for hepatocellularcarcinoma. Cancers. (2022) 14:504. doi: 10.3390/cancers140305042. Frau C, Loi R, Petrelli A, Perra A, Menegon S, Kowalik MA, etal. Local hypothyroidism favors the progression of preneoplasticlesions to hepatocellular carcinoma in rats. Hepatology. (2015)61:249–59. doi: 10.1002/hep.273993. Mohamad B, Shah V, Onyshchenko M, Elshamy M, Aucejo F, Lopez R,et al. Characterization of hepatocellular carcinoma (HCC) in non-alcoholicfatty liver disease (NAFLD) patients without cirrhosis. Hepatol Int. (2016)10:632–9. doi: 10.1007/s12072-015-9679-04. Kowalik MA, Puliga E, Cabras L, Sulas P, Petrelli A, Perra A, et al. Thyroidhormone inhibits hepatocellular carcinoma progression via induction ofdifferentiation and metabolic reprogramming. J Hepatol. (2020) 72:1159–69. doi: 10.1016/j.jhep.2019.12.018Frontiers in Medicine | www.frontiersin.org 2 June 2022 | Volume 9 | Article 944769Perra and Plateroti Editorial: Targeting Thyroid Hormone Pathways5. Duntas LH, Brenta G. A renewed focus on the association betweenthyroid hormones and lipid metabolism. Front Endocrinol. (2018)9:511. doi: 10.3389/fendo.2018.005116. Alonso-Merino E, Martín Orozco R, Ruíz-Llorente L, Martínez-Iglesias OA,Velasco-Martín JP, Montero-Pedrazuela A, et al. Thyroid hormones inhibitTGF-β signaling and attenuate fibrotic responses. Proc Natl Acad Sci USA.(2016) 113:E3451–60. doi: 10.1073/pnas.15061131137. Perra A, Kowalik MA, Pibiri M, Ledda-Columbano GM, Columbano A.Thyroid hormone receptor ligands induce regression of rat preneoplasticliver lesions causing their reversion to a differentiated phenotype.Hepatology.(2009) 49:1287–96. doi: 10.1002/hep.227508. Caddeo A, Kowalik MA, Serra M, Runfola M, Bacci A, Rapposelli S, etal. TG68, a novel thyroid hormone receptor-β agonist for the treatment ofNAFLD. Int J Mol Sci. (2021) 22:13105. doi: 10.3390/ijms2223131059. Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, et al.Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis:a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.Lancet. (2019) 394:2012–24. doi: 10.1016/S0140-6736(19)32517-610. Fernandez M, Giuliani A, Pirondi S, D’Intino G, Giardino L, Aloe L, etal. Thyroid hormone administration enhances remyelination in chronicdemyelinating inflammatory disease. Proc Natl Acad Sci USA. (2004)101:16363–8. doi: 10.1073/pnas.0407262101Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Publisher’s Note: All claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations, or those ofthe publisher, the editors and the reviewers. Any product that may be evaluated inthis article, or claim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.Copyright © 2022 Perra and Plateroti. This is an open-access article distributedunder the terms of the Creative Commons Attribution License (CC BY). The use,distribution or reproduction in other forums is permitted, provided the originalauthor(s) and the copyright owner(s) are credited and that the original publicationin this journal is cited, in accordance with accepted academic practice. No use,distribution or reproduction is permitted which does not comply with these terms.Frontiers in Medicine | www.frontiersin.org 3 June 2022 | Volume 9 | Article 944769

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Editorial: Targeting Thyroid Hormone-Dependent Pathways in Proliferative and Degenerative Disorders

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