Numerous studies have identified age threshold as a predictive factor for RAIR-DTC. Retrospective analyses by Shobab et al. and Chen et al. found that patients over 45 years old had a higher odds ratio (OR) for developing RAIR-DTC (34, 35). Similarly, Li et al. reported an increased incidence of RAIR in patients over 55 years of age (29). Interestingly, Saie et al. noted that age thresholds of 45 and 75 years were predictive of OS, but not PFS, in RAIR-DTC patients (36). Regarding sex, Wang et al. observed a significantly higher proportion of male RAIR patients compared to females (P < 0.05), with logistic regression confirming male sex as a predictive factor (37). In contrast, Liu et al. found a higher proportion of female RAIR patients, although the difference was not statistically significant (38).

Shobab et al. analyzed the relationship between ethnicity and RAIR-DTC, finding that individuals of white ethnicity had a lower OR for RAIR, whereas those of black ethnicity had a higher OR (34). In a germline genetic analysis comparing African American and Caucasian patients, Hurst et al. identified specific haplotypes—TG, BRCA1, and NSMCE2—that were associated with RAIR occurrence in African American patients with over 80% African ancestry (39). Regarding lifestyle factors, Li et al. reported that smoking and a body mass index (BMI) of 24 kg/m² or higher were associated with an increased risk of RAIR development (29).

The RAS gene family (NRAS, HRAS, KRAS) encodes GTP-binding proteins, and activating mutations in these genes are frequently observed in TCs, with an overall prevalence of approximately 35.4%—NRAS accounting for 69.47%, HRAS for 25.83%, and KRAS for 6.92% (40). Studies by Bond et al., Monaco et al., and Portella et al. have shown that RAS mutations reduce the expression of thyroid differentiation markers such as thyroglobulin (TG), thyroid peroxidase (TPO), and the thyrotropin receptor (TSHR), while promoting increased thyroid cell proliferation. Although RAS mutations alone are insufficient to drive full malignant transformation, the presence of co-occurring mutations, particularly TERT promoter mutations, has been linked to more aggressive tumor phenotypes and increased mortality in RAS-mutant DTCs (41, 42). Furthermore, Saavedra et al. demonstrated that RAS mutations promote chromosomal instability in PCCL3 cells, potentially facilitating malignant progression by increasing susceptibility to additional genetic alterations (43).

BRAF, a member of the RAF kinase family, plays a key role in cell signaling pathways that regulate proliferation and survival. The BRAF^V600E mutation, which is more prevalent in PTCs than RAS mutations, drives oncogenesis by promoting uncontrolled cell proliferation (44). Dong et al. demonstrated that BRAF^V600E significantly reduced sodium-iodide symporter (NIS) expression in a subset of PTC patients without Hashimoto’s thyroiditis (P = 0.046) (45). Additionally, Makboul et al., in an analysis of clinical data from 78 PTC patients, found that BRAF^V600E was significantly associated with increased tumor size, lymphovascular invasion, and lymph node metastasis (46). Furthermore, both Mu et al. and Wang et al. identified BRAF^V600E as an independent predictor of RAIR-DTC (32, 35).

The TERT gene encodes the catalytic subunit of telomerase, an enzyme critical for maintaining telomere length and promoting cellular immortality. Mutations in the TERT promoter are commonly observed in DTC and are strongly associated with tumor dedifferentiation (47). Yang et al. conducted a retrospective analysis of 66 DTC cases with distant metastases and found that TERT promoter mutations were more strongly associated with reduced RAI avidity and negative RAI uptake compared to BRAF^V600E mutations (48). Similarly, Tan et al., in a cohort of 243 patients (non-RAIR: N = 212; RAIR: N = 31), reported that TERT promoter mutations accelerated progression to RAIR (49). Parvathareddy et al. also demonstrated a significant association between TERT promoter mutations and RAIR-DTC through multivariate analysis of 268 RAIR-DTC cases (30). Furthermore, Ju et al., using next-generation sequencing on 278 RAIR-DTC tumor samples, confirmed that TERT promoter mutations were the predominant genetic drivers of RAIR in adults (50).

The RET proto-oncogene, located at chromosome 10q11.2, encodes a receptor tyrosine kinase involved in several TC subtypes. RET rearrangements, present in approximately 20% of PTCs, promote dedifferentiation of DTCs and significantly impair RAI uptake and metabolism (51). Notably, thyroid cells in children are more vulnerable to ionizing radiation and have reduced DNA repair capacity, making them more susceptible to RET rearrangements and subsequent malignant transformation (52). These rearrangements play a critical role in compromising RAI responsiveness and contribute to the development of RAIR-DTC. Therefore, detecting RET mutations and fusions in pediatric TC cases holds important clinical significance.

The TRK family of transmembrane receptorsranes. TRKB, and TRKC,to encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. NTRK gene fusions have oncogenic potential in both neural and non-neural tissues (53). In DTCs, the most common fusion types include ETV6udeEN. (64.4%), TPM34%),N. (8.4%), and SQSTM1,N.CI (6.8%) (54). Notably, non-secretory TCs characterized by multinodular growth of eosinophilic cells harboring NTRK fusions are often associated with more aggressive clinical behavior. Chu et al. reported that NTRK fusion–positive. PTCs frequently exhibit high-grade features such as elevated mitotic activity, extensive lymphatic invasion, and extrathyroidal extension (ETE) (55). Similarly, Pekova et al. found that thyroid cancers with NTRK1 fusions show increased lymphatic invasion and distant lymph node metastases (54). Both NTRK1 and NTRK3 fusions have emerged as valuable diagnostic and prognostic biomarkers in TC.

Li et al. and Luo et al. conducted retrospective analyses involving approximately 6,594 cases and found that several histopathological subtypes, such as extrathyroidal extension (ETE), tall cell variant, diffuse sclerosing and hobnail variants of PTC, follicular thyroid carcinoma (FTC, including Hürthle cell), and poorly differentiated thyroid carcinoma (PDTC), are significantly associated with RAIR-DTC. These features serve as independent predictors for the development of RAIR-DTC (29, 56).

Li et al. found that the number of lymph node metastases (≥4), lymph node metastasis rate (≥53%), and pN stage (N1) were significantly and positively associated with the prevalence of RAIR-DTC (29). In a comparative analysis of 159 RAIR cases and 759 non-RAIR cases, Schubert et al. identified vascular invasion, synchronous cervical, pulmonary, and bone metastases at initial diagnosis, as well as cervical and pulmonary recurrence during follow-up, as independent predictive factors for RAIR development (31).

Thyroglobulin (TG) is an effective biomarker for monitoring clinical outcomes in patients with distant metastatic DTC. Sa et al. reported that a post-I¹³¹ TG reduction of less than 25.3% in these patients predicted a poor response to subsequent I¹³¹ therapy (58). In a retrospective analysis of 876 DTC cases (786 non-RAIR vs. 90 RAIR), Cheng et al. found that elevated preoperative TG (pre-TG) levels were significantly associated with RAIR development and served as an independent predictor (59). Meng et al. developed a nomogram model using a cutoff value of △s-TG/△s-TSH < 1.5(where △s-TG represents the difference between pre-treatment stimulated and suppressed TG, and △s-TSH denotes the difference in TSH levels before and after treatment) to predict RAIR-DTC progression (60). Importantly, serum TG measurements should be interpreted alongside anti-thyroglobulin antibody (TGAb) levels, as TGAb can interfere with TG accuracy.

Nilsson et al. demonstrated a positive correlation between thyroid peroxidase (TPO) expression and RAI avidity by analyzing surgical specimens, including primary tumors and lymph node metastases, from 28 DTC patients (61). Similarly, Zelinskaya et al., through immunocytochemical analysis of 104 metastatic DTC lesions, confirmed that the absence of TPO expression is a predictive marker for RAIR development (62).

Jeong et al. reported that significantly higher serum Cyfra 21.1 levels in patients with metastatic TCs compared to those with non-metastatic disease and healthy controls (distant metastasis: N = 51; non-distant metastasis: N = 76; P = 0.012). Among the metastatic group, RAIR patients (N = 13) exhibited significantly higher Cyfra 21.1 levels than RAI-avid patients (N = 12; P = 0.047), suggesting its potential as a biomarker for RAIR-DTC, particularly in cases where TG is undetectable (63). Additionally, Tian et al. demonstrated an inverse correlation between lactate dehydrogenase A (LDHA) expression and RAI uptake in a cohort of 69 DTC patients, indicating a potential role of LDHA in mediating RAI resistance (64).

Pecce et al. reported that miR-139-5p was significantly downregulated in RAIR-DTC patients (N = 14) compared to non-RAIR-DTC patients (N = 12). Overexpression of miR-139-5p enhanced NIS expression and RAI uptake, suggesting its potential as a predictive biomarker for RAIR-DTC (65). Additionally, Collina et al. found that a strong association between high expression of anexelekto (AXL), BRAF^V600E mutations, and RAIR occurrence (P < 0.0001) in a cohort of 110 PTC patients and 5 controls. Their findings indicate that elevated AXL expression may contribute to RAIR by suppressing NIS expression, thus serving as a potential predictive marker (66). Liu et al. also identified that a significant correlation between the low density lipoprotein-cholesterol-total cholesterol ratio (LDL-Ch/TCh) ratio and RAIR incidence in TC patients (RAIR: N = 12; controls: N = 24) (67).

Studies have established a connection between diabetes mellitus and thyroid disorders, indicating that diabetes related traits such as elevated insulin levels, insulin resistance, metabolic dysregulation, and oxidative stress may exacerbate the severity of thyroid conditions (76–78). Zhang et al. utilized the TyG index, a marker of insulin resistance, to analyze a cohort of 47,710 subjects, revealing a significant increase in the prevalence of thyroid disorders and the risk of subclinical hypothyroidism associated with higher TyG index values (79). Moreover, impaired sensitivity to TSH or reduced TSH levels in individuals with diabetes contribute to metabolic dysregulation, resulting in decreased RAI sensitivity and diminished expression of NIS (80, 81). The oxidative stress induced by diabetes, characterized by elevated lipid peroxides and downregulated TSH levels, disrupts thyroide redox balance of the thyroid gland (81, 82). Azouzi et al. demonstrated that the upregulation of reactive oxygen species (ROS) can lead to the downregulation of NIS in DTC cells (78), suggesting that diabetes may promote the RAIR-DTC development.

In addition to diabetes mellitus, anti-diabetic medications such as Metformin, an AMPK agonist approved by the U.S. Food and Drug Administration (FDA), may have varying effects patients. While some studies indicate that metformin reduces tumor volume in diabetic patients with RAIR-DTC (83), others report a decreases in NIS expression and iodine uptake in vitro ( 84). Consequently, the use of Metformin in diabetic patients with RAIR-DTC may yield antagonistic effects through AMPK activation.

Evidence suggests that prolonged RAI therapy exceeding 100 mCi may increase the risk of acute or chronic myeloid leukemia (AML or CML) in DTC patients, particularly males. This risk is potentially linked to ROS induced oxidative stress and subsequent DNA damage (71, 74, 85). Supporting this mechanism, Rajeshwari et al. observed elevated lipid peroxidation and protein oxidation in AML (N=30) and CML (N=30) patients compared to controls (N=13) (86). Similarly, Zhou et al. and Pascu et al. emphasized oxidative stress’s role in the etiology and treatment of AML and CML (87, 88). Furthermore, Cazarin et al. noted that ROS can alter the expression and function of the NIS in thyrocytes and TC cells (89).

Nilotinib, an FDA-approved BCR-ABL inhibitor for CML, enhances TC sensitivity to RAI by inducing autophagy through PI3K/Akt pathway inhibition (90, 91). However, it also activates AMPK, which promotes NIS degradation. This reduces RAI uptake and can induce RAIR (92, 93).

Yu et al. found that altered thyroid hormone (TH) sensitivity—specifically reduced central sensitivity and increased peripheral sensitivity—is associated with a heightened risk of hypertension in patients with coronary heart disease (N=34,310). Logistic regression analysis revealed an inverse relationship between central thyroid resistance (reflected by the TSH index) and hypertension risk, alongside a positive correlation between the FT3/FT4 ratio (indicating peripheral sensitivity) and hypertension risk (94). Separately, MKIs like sorafenib and Lenvatinib, which inhibit the VEGF axis, are associated with hypertension in advanced DTC (72, 95). Furthermore, although less common, Kitamura et al. observed that sternal or mediastinal lymph node metastases in metastatic TC can compress the vena cava, causing hypotension and sudden death (75). Collectively, these findings suggest that blood pressure dysregulation may influence the incidence or progression of RAIR-DTC.

In the management of blood pressure disorders in patients with DTC, anti-hypertensive medications such as Valsartan, Captopril, and Nifedipine, along with anti-hypotensive drug Etilefrine, which is known for its activation of the AMPK pathway, are used (96–99). Consequently, these medications may influence the expression of the NIS and RAI uptake through AMPK activation, potentially impacting the development and progression of RAIR-DTC.

Mitogen-activated protein kinase (MAPK) cascades in mammalian cells consist of three major families: extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38/stress-activated protein kinases (SAPKs) (106). The MAPK pathway, a downstream branch of BRAF signaling, significantly influences the expression of key genes involved in thyroid hormone biosynthesis, including NIS, TPO, and TG, and plays a crucial role in the progression of RAIR-DTC (107, 108). Liu et al. demonstrated that inhibiting MEK or silencing the BRAF^V600E mutation in PCCL3 cells (a rat thyroid cell line) restored the expression of iodide-metabolizing genes (109). Furthermore, BRAF^V600E induced deacetylation of nucleotides −297/−107 in the rat NIS promoter and −692/−370 in the human NIS promoter contributes to NIS gene silencing (110). Overexpression of miR-20b has been shown to reduce cell viability and migration in human TC cells and to suppress tumor growth in xenografts by directly targeting SOS1 and ERK2, thereby inhibiting the MAPK/ERK pathway (111). Similarly, Shen et al. reported that miR-106a overexpression decreased NIS expression and RAI uptake in TC cells by directly targeting retinoic acid receptor beta (RARB) and activating the MAPK pathway in vitro ( 112). Overall, BRAF^V600E mediated hyperactivation of the MAPK pathway plays a key role in suppressing NIS expression.

Besides regulating cell growth, transcription, and translation, the phosphoinositide 3-kinase (PI3K) pathway plays a significant role in the pathogenesis of RAIR-DTC (113). Bibian et al. demonstrated that IGF1-mediated activation of PI3K markedly inhibited TSH-dependent NIS transcription in FRTL5 cells, a rat thyroid cell line (114). Similarly, Kogai et al. showed that the PI3K inhibitor LY294002 significantly increased iodide uptake and enhanced PAX8 expression in PCCL3 cells by stimulating NIS post-translational regulation (115). Pharmacological inhibition of PI3K led to approximately a 3.5-fold increase in exogenous NIS expression and iodine uptake in BHP 2–7 cells, which harbor the RET/PTC1 rearrangement (115). Liu et al. found that inhibition of Akt using Akti-1/2 in PCCL3 cells did not increase NIS protein expression but significantly reduced iodide efflux and enhanced the affinity between iodine and NIS, thereby promoting RAI uptake (116). Rapamycin, an mTOR inhibitor, improved iodine uptake and reduced cell viability in PCCL3 cells, despite not elevating NIS protein levels. Its synthetic analog, everolimus, similarly enhanced thyroid iodine uptake in vivo (117). Moreover, Plantinga et al. reported that rapamycin increased both mRNA and protein levels of human NIS (hNIS) and RAI uptake capacity in TC cells by inhibiting mTOR via transcriptional upregulation of TTF1 expression (118). Additionally, Chen et al. found that overexpression of small nucleolar RNA host gene 7 upregulated dipeptidyl peptidase 4 (DPP4), promoting TC cell proliferation and I¹³¹ resistance through activation of the PI3K/Akt pathway (119). In summary, these findings support the conclusion that aberrant activation of the PI3K/Akt/mTOR pathway reduces NIS mediated radioiodine accumulation in the thyroid gland.

The AMP-activated protein kinase (AMPK) signaling pathway is activated in response to cellular energy depletion and is notably upregulated in PTCs, contributing to TC progression (92). The AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) significantly reduced NIS mRNA and protein expression in PCCL3 cells. However, this effect was reversed by TSH-induced activation of the cyclic adenosine monophosphate (cAMP)/protein kinase A pathway or treatment with bafilomycin A1, both of which inhibited AMPK signaling (92, 93). Gonçalves et al. demonstrated that rutin increased NIS mRNA and protein expression and reduced RAI efflux both in vitro and in vivo by inhibiting the AMPK pathway and ROS generation (120, 121). Additionally, Compound C, an AMPK inhibitor, enhanced NIS expression by promoting activation of the cyclic AMP response element (CRE) in the NIS promoter, through suppression of AMPK signaling (84). In summary, aberrant activation of the AMPK pathway can downregulate RAI uptake in both non-neoplastic thyroid follicular cells and TC cells.

Activation of the transforming growth factor-beta (TGF-β) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways also negatively regulates NIS expression and RAI uptake in the thyroid gland. Further details are available in reference (104).