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Thyroid Disorders: From Physiological Regulation to Targeted Cancer Therapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 31 January 2027 | Viewed by 663

Special Issue Editor


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Guest Editor
Radiobiology Department, National Atomic Energy Commission (CNEA), Buenos Aires C1429 BNP, Argentina
Interests: thyroid autoregulation and redox homeostasis, with particular emphasis on oxidative stress, iodolipid signaling, and iodine metabolism; the role of selenium in thyroid physiology and disease, as well as in the molecular mechanisms underlying thyroid cancer development and progression

Special Issue Information

Dear Colleagues,

The thyroid gland is a highly specialized endocrine organ that regulates metabolism, growth, and tissue homeostasis through the synthesis and action of thyroid hormones. These functions depend on tightly controlled molecular mechanisms governing iodide uptake and metabolism, hormone biosynthesis, redox balance, and autoregulatory responses that allow the gland to adapt to physiological and environmental demands. Alterations in these regulatory processes not only underlie functional thyroid disorders but also contribute to thyroid tumorigenesis, disease progression, and therapeutic responsiveness. The disruption of these physiological regulatory networks represents a key mechanistic link between normal thyroid function and malignant transformation. In this context, while most differentiated thyroid cancers can be successfully managed with surgery and radioiodine therapy, a clinically relevant subset of tumors becomes refractory to radioiodine due to loss of differentiation, impaired iodide metabolism, and dysregulated redox and signaling pathways. Poorly differentiated and anaplastic thyroid carcinomas remain associated with aggressive behavior and limited treatment options, underscoring the need for improved molecular stratification and innovative therapeutic approaches.

This Special Issue aims to provide an integrative platform with a primary focus on thyroid cancer and its treatment, while explicitly positioning thyroid physiology as a molecular framework shaping tumor biology and therapeutic response. We welcome contributions addressing oncogenic signaling pathways, tumor microenvironment and immune interactions, mechanisms of dedifferentiation and therapy resistance, as well as clinical and translational studies on targeted therapies, radionuclide treatments, and emerging therapeutic approaches. In particular, studies exploring the role of thyroid hormones, iodine metabolism, oxidative stress, and redox regulation in both normal thyroid biology and cancer development are especially encouraged, given their strong translational potential. By bridging basic, translational, and clinical research, this Special Issue seeks to advance the molecular understanding of thyroid cancer and to foster the development of more effective and personalized therapeutic strategies for patients with thyroid malignancies.

Dr. Lisa Thomasz
Guest Editor

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Keywords

  • thyroid autoregulation
  • oxidative stress
  • iodide excess
  • sodium-iodide symporter (NIS)
  • thyroid cancer
  • autoimmune thyroid disease
  • thyroid tumor microenvironment
  • dedifferentiation mechanisms
  • targeted therapies
  • radionuclide therapy

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Published Papers (1 paper)

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Research

24 pages, 4402 KB  
Article
New Insights into Iodide Transport Defects (ITDs) from the Characterization of a Heterozygous NIS Missense Variant (p.G288S) Identified in a Family with Thyroid Dysfunction During Pregnancy
by Maddi Garate-Etxeberria, Mari Paz Lopez-Molina, Rafael Hortiguela, Pouya Alikhani, María De la Calle, Custodia García-Jimenez, Jose Carlos Moreno and Antonio De la Vieja
Int. J. Mol. Sci. 2026, 27(12), 5160; https://doi.org/10.3390/ijms27125160 - 6 Jun 2026
Viewed by 228
Abstract
The Na+/I symporter (NIS) is the plasma membrane (PM) protein that actively mediates iodide (I) transport into the thyroid gland. Pathogenic variants in the SLC5A5 gene cause iodide transport defects (ITDs). A heterozygous G288S NIS variant was identified [...] Read more.
The Na+/I symporter (NIS) is the plasma membrane (PM) protein that actively mediates iodide (I) transport into the thyroid gland. Pathogenic variants in the SLC5A5 gene cause iodide transport defects (ITDs). A heterozygous G288S NIS variant was identified in a Spanish family in which female carriers developed thyroid dysfunction during pregnancy. Here, we characterized the functional significance of the G288S variant and other substitutions at residue 288 of human NIS. Human NIS (hNIS) expression and maturation were analyzed by immunoblotting, its subcellular localization was analyzed by immunofluorescence and flow cytometry, and its activity was analyzed by radioiodide uptake assays. The G288S variant does not affect hNIS maturation, membrane trafficking, or I uptake capacity, but significantly reduces I affinity while preserving substantial transport activity. In contrast, substitutions introducing charged residues (arginine, aspartic acid, or glutamic acid) or proline severely disrupted NIS maturation, plasma membrane targeting, and iodide transport. Because the variant was identified in heterozygosity, we evaluated residue 288 substitutions under heterozygous-like conditions. Co-expression of the patient-derived G288S variant with WT NIS produced an intermediate apparent Km without reducing Vmax compared with WT, consistent with a modest co-expression-dependent kinetic effect rather than a strong dominant-negative mechanism. In contrast, the severely disruptive G288E substitution reduced cell-surface NIS expression under co-expression conditions, providing proof-of-principle evidence that severe alteration of residue 288 can impair NIS plasma membrane delivery. These findings highlight residue 288 as a key determinant of hNIS functionality and underscore the need to carefully evaluate heterozygous SLC5A5/NIS variants, as they may become clinically relevant under conditions of increased physiological iodine demand and contribute to partial iodide transport impairment. Full article
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