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Review

Molecular Mechanisms of Radioiodine Refractoriness in Differentiated Thyroid Cancer: Focus on Sodium/Iodide Symporter Dysregulation

by
Vladimir D. Rokashkov
1,
Liudmila V. Spirina
1,2,*,
Natalya V. Tarasenko
1 and
Svetlana Yu. Chizhevskaya
1,2
1
Biochemistry and Molecular Biology Division, Siberian State Medical University, 2 Moskovsky Trakt, Tomsk 634050, Russia
2
Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Kooperativny Street, Tomsk 634050, Russia
*
Author to whom correspondence should be addressed.
Curr. Issues Mol. Biol. 2026, 48(4), 362; https://doi.org/10.3390/cimb48040362
Submission received: 18 February 2026 / Revised: 26 March 2026 / Accepted: 26 March 2026 / Published: 31 March 2026
(This article belongs to the Special Issue Molecular Markers of Tumor Response and Toxicity of Antitumor Therapy)
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Abstract

The sodium/iodide symporter (NIS/SLC5A5) is a major determinant of radioiodine therapy efficacy in differentiated thyroid cancer (DTC). This narrative review examines the molecular mechanisms underlying NIS dysregulation and radioiodine refractoriness in DTC. Reduced NIS expression or function in radioiodine-refractory DTC is associated with multiple mechanisms, including transcriptional suppression linked to MAPK/ERK and PI3K/AKT pathway activation and disruption of thyroid differentiation programs; epigenetic silencing involving SLC5A5 regulatory regions; impaired protein trafficking and membrane localization; and post-transcriptional regulation by microRNAs such as miR-221-3p, miR-222-3p, miR-146b-3p, and miR-204-5p. Genetic alterations including BRAF V600E and TERT promoter mutations are associated with dedifferentiated tumor phenotypes and poor radioiodine response. Redifferentiation approaches using MAPK pathway inhibitors such as selumetinib and dabrafenib can restore iodine uptake in selected patients, although the overall clinical applicability of these strategies remains under evaluation. A better understanding of these mechanisms may support improved biologic stratification and more selective therapeutic decision-making in radioiodine-refractory DTC.
Keywords: thyroid cancer; NIS (sodium/iodide symporter); microRNAs; radioiodine refractoriness; biomarkers thyroid cancer; NIS (sodium/iodide symporter); microRNAs; radioiodine refractoriness; biomarkers
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MDPI and ACS Style

Rokashkov, V.D.; Spirina, L.V.; Tarasenko, N.V.; Chizhevskaya, S.Y. Molecular Mechanisms of Radioiodine Refractoriness in Differentiated Thyroid Cancer: Focus on Sodium/Iodide Symporter Dysregulation. Curr. Issues Mol. Biol. 2026, 48, 362. https://doi.org/10.3390/cimb48040362

AMA Style

Rokashkov VD, Spirina LV, Tarasenko NV, Chizhevskaya SY. Molecular Mechanisms of Radioiodine Refractoriness in Differentiated Thyroid Cancer: Focus on Sodium/Iodide Symporter Dysregulation. Current Issues in Molecular Biology. 2026; 48(4):362. https://doi.org/10.3390/cimb48040362

Chicago/Turabian Style

Rokashkov, Vladimir D., Liudmila V. Spirina, Natalya V. Tarasenko, and Svetlana Yu. Chizhevskaya. 2026. "Molecular Mechanisms of Radioiodine Refractoriness in Differentiated Thyroid Cancer: Focus on Sodium/Iodide Symporter Dysregulation" Current Issues in Molecular Biology 48, no. 4: 362. https://doi.org/10.3390/cimb48040362

APA Style

Rokashkov, V. D., Spirina, L. V., Tarasenko, N. V., & Chizhevskaya, S. Y. (2026). Molecular Mechanisms of Radioiodine Refractoriness in Differentiated Thyroid Cancer: Focus on Sodium/Iodide Symporter Dysregulation. Current Issues in Molecular Biology, 48(4), 362. https://doi.org/10.3390/cimb48040362

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