Role of interleukin 17 and T helper cells 17 cells as a new immune target and signalling in the pathogenesis and treatment of autoimmune thyroid diseases

Abstract

Objective

This study aims to systematically review the molecular and cellular mechanisms by which the interleukin 17 (IL-17)/T helper cells (Th17) signalling axis contributes to Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), with particular focus on IL-17/Th17/T regulatory cells (Treg) balance, and to summarize the development of IL-17-targeted therapies for autoimmune thyroid disease (AITD).

Methods

A comprehensive literature review (up to 2025) was conducted, encompassing human studies, animal models, and pre-clinical investigations related to IL-17/Th17 biology in AITD.

Results

IL-17 levels are elevated in both untreated and intractable GD. IL-17/IL-17RA signalling enhances the expression of IL-6, chemokine CXC ligand 10, and intercellular cell adhesion molecule-1, thereby amplifying thyroid inflammation. The IL-23/IL-17 axis and Th17/Treg imbalance are strongly associated with thyroid-associated ophthalmopathy. Serum and tissue IL-17 concentrations correlate positively with TPOAb or TgAb titres and early fibrosis, while Th17 predominance precedes Th1-mediated tissue destruction. Excessive iodine intake further drives naïve Tregs toward Th17 differentiation. Shared TGF-β signalling drives the reciprocal development of Th17 and Treg cells, with retinoid-related orphan receptor gamma t and Forkhead box protein P3 acting as molecular switches. Disruption of this balance contributes to the progression of AITD. Several pre-clinical agents (JiaYanKangTai, Yanghe decoction, LY294002) have been found to ameliorate experimental autoimmune thyroiditis by inhibiting IL-17 signalling or restoring Th17/Treg equilibrium; however, clinical translation remains limited.

Conclusions

IL-23/IL-17 axis and Th17/Treg imbalance are critical checkpoints in the AITD pathogenesis. IL-17 represents a promising, yet still experimental immunotherapeutic target, warranting rigorous clinical investigation.

1. Introduction

Autoimmune thyroid disease (AITD) is one of the common organ-specific autoimmune disorders of the endocrine system in clinical practice [1]. It is primarily characterized by regulatory T cell (Treg)-mediated thyroid dysfunction, autoantibody production, and reactive lymphocyte infiltration, which can ultimately lead to systemic multi-organ damage [2]. Currently, AITD primarily includes Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). The atrophic thyroiditis, silent thyroiditis, and postpartum thyroiditis were also described in the AITDs [3]. Previous studies have indicated that the global prevalence of AITD is approximately 2%–5%, and the proportion of patients who exhibit only positive antithyroid antibodies is higher [3,4]. For instance, approximately 14% of patients exhibit positive thyroid antibodies, while the prevalence of GD is approximately 0.5% in China [4]. The specific pathogenesis of AITD remains unclear. According to the different clinical symptoms of AITD, including HT manifested as hypothyroidism and GD manifested as hyperthyroidism, a single influencing factor does not seem to be able to explain this complex mechanism [3,5]. The current view is that its pathogenesis involves multiple aspects, including immunity, genetics, and environment, among which immune factors are closely associated with the occurrence of AITD [6]. Extensive studies have been conducted to investigate the potential mechanisms of T lymphocytes and the cytokines they secrete [6,7].

Interleukin 17 (IL-17) is a 155-amino acid cytokine, first identified in mouse lymphocytes, and primarily exists in the form of a homodimer [8]. IL-17 is primarily secreted by activated T helper (Th17) cells, although CD8+ Tregs and natural killer cells can also produce small amounts. Currently, the IL-17 family comprises six different subtypes (IL-17A to IL-17F) that act on five different receptors (IL-17RA to IL-17RE) [9]. Among them, IL-17A, as the most important effector of the IL-17 family, is often referred to as a broad term encompassing IL-17, which plays a crucial role in regulating immune responses [10,11]. Additionally, IL-17F, which is produced by helper Tregs, shares approximately 55% sequence homology with IL-17A. IL-17A and IL-17F can activate IL-17R through signal transduction in the form of homodimers or heterodimers [12,13]. Overall, IL-17 is recognized as a pro-inflammatory cytokine involved in the body’s immune regulation, tissue repair, cancer progression, and inflammation. Previous studies have indicated that IL-17 exerts immunomodulatory effects by recruiting other immune cells, regulating the expression of pro-inflammatory cytokines, and activating signalling pathways such as NF-kB and MAPK [14].

Recently, the correlation between IL-17 and autoimmune diseases, including AITD, has been widely studied. However, a more comprehensive review is required to summarize the signal transduction mechanism of IL-17, to enhance the efficacy of IL-17 therapy in the treatment of AITD [3,15]. In this review, we report the current molecular mechanism of the IL-17 signalling pathway in AITD under pathological conditions, with a primary focus on the balance of IL-17/Th17/Tregs, and attempt to summarize the development of IL-17-targeted therapies for AITD. Two authors independently searched PubMed, EMBASE, Web of Science, and Cochrane databases up to May 2025 for relevant literature on the role of Th17 cells and IL-17 in AITD. Search terms included combinations of ‘Th17 OR IL-17 OR IL-17A OR cytokine,’ ‘AITD OR GD OR HT OR AITD OR GD OR HT,’ and the Boolean operator AND was used. We searched for articles published in English only. All retrieved titles and abstracts were screened for relevance, and duplicate articles, letters, commentaries, case reports, and unrelated studies were excluded. The remaining full-text articles were then reviewed to address this topic. Figure 1 provides an overview of current research on the mechanisms of IL-17 in AITD.

Figure 1.

The mechanism of IL-17 and immune cells targeting AITD (partial). IL-17 can mediate its immunoregulatory functions by recruiting DC, Th17, CD4 + T cell, and Treg cells, inducing the expression of pro-inflammatory cytokines like IL-23, CXCL10, ICAM-1, CD40L, IFN-c, IL-10, IL-β, IL-18 and so on. Activating signalling pathways such as NF-κB, MAPK, ROR-γt, Notch, PI3K/AKT/mTOR, ERK. The engagement of IL-23R on Th17 cells triggers a feedback stimulation of PGE2, EP2, EP4, IL-23 production, which establishes a cyclic pathway that amplifies Th17 differentiation. Some drugs such as LY294002, JYKT, Yanghe decoction can mediate signals and promote Th17 cells to secrete IL-17A, promotes IL-17 attack on thyroid. AITDs: Autoimmune thyroid diseases; IL-17: interleukin-17; Th17: T helper cell 17; Treg: Regulatory T cells; DC: Dendritic cell; ROR-γt: retinoid-related orphan receptor gamma t; FoxP3: Forkhead box protein P3; Stat3: Signal transducer and activator of transcription 3; PGE2: Prostaglandin E2; CXCL10: Chemokine CXC ligand 10; ICAM-1: Intercellular cell adhesion molecule-1; NF-κB: Nuclear factor-kappa B; MARK: Mitogen-activated protein kinase; NLRP3: NOD-like receptor family, pyrin domain containing 3; PI3K: Phosphatidylinositol 3-kinase; mTORC1: mechanistic target of rapamycin complex 1; TRAF6: TNF receptor associated factor 6; ERK1/2: Extracellular regulated protein kinases 1/2; JYKT: JiaYanKangTai.

2. IL-17 family of cytokines in AITDs

2.1. Role of IL-17 in GD

GD is an autoimmune organ-specific thyroid disorder caused by genetic and environmental factors. Approximately 2% of women and 0.2% of men globally suffer from this disease, and its incidence has recently indicated a clear upward trend [16,17]. CD4 + T helper lymphocytes play a crucial role in the development of GD. Previous studies have often been limited to Th1 cells and Th2 cells; however, recent research has found that Th17 cells, which are CD4+ lymphocytes that secrete high levels of IL-17, play an essential role. IL-17, especially IL-17A, can induce the migration of white blood cells to the inflammatory site by attracting a large number of cytokines and chemokines, including IL-1, IL-6, and cell-adhesion factors, thereby playing a crucial role in various inflammatory and autoimmune disorders [18]. Li et al. [18] have collected peripheral blood samples to detect serum levels of IL-17 from untreated GD (have no antithyroid drug treatment), intractable GD (have antithyroid drug treatment for at least five years but still exhibit positive TRAbs), remission group (euthyroid status, negative TRAbs over two years following stopping antithyroid drug treatment), and healthy group (euthyroid status). The results indicated that serum IL-17 levels are significantly elevated in the intractable group and the untreated group, particularly in intractable GD, indicating the potential role of IL-17 in GD treatment options. Mechanistically, IL-17 induces the upregulation of IL-6, chemokine CXC ligand 10, and intercellular cell adhesion molecule-1 expression through the IL-17RA-mediated signalling pathway, thereby improving the inflammatory response in GD. Additionally, some studies have suggested that the IL-17F/rs763780 polymorphism may positively influence susceptibility to AITD, whereas the IL-17A/rs3819025 SNP may be a protective factor for GD in the Chinese population [19]. Research has also demonstrated that IL-17 can be involved in the pathogenesis of autoimmune thyroid damage by activating the NF-κB signalling pathway and inducing the production and release of cytokines, including tumour necrosis factor-alpha (TNF-α), IL-6, and IFN-γ [20]. Zheng et al. demonstrated that the IL-23/IL-17 axis can generate the secretion of inflammatory factors, cytokines, and chemokines by regulating the retinoid-related orphan receptor gamma t (ROR-γt) [21]. During inflammation, IL-23 can induce the aggregation of Th17 cells, as the absence of IL-23 will affect the production of Th17 cells and their cytokines. Additionally, IL-23 may bind to the IL-23 receptor on the cell surface through a positive feedback loop, thereby improving the expression of IL-6, IL-1β, and TNF-α, and subsequently promoting Th17 cell differentiation and IL-17 secretion. Conversely, the IL-17 receptor on the surface of dendritic cells can also bind to IL-17, leading to the production of a large amount of IL-23, further promoting Th17 cell differentiation and IL-17 secretion [21,22].

Clinically, about 20%–50% of patients with GD are complicated by thyroid-associated ophthalmopathy (TAO). Patients with TAO typically experience symptoms, including dry eyes, foreign body sensation, excessive tearing, diplopia, and eye pain. Significantly reduces the quality of life of patients with TAO [23]. In the early stage of TAO, multiple immune cells and inflammatory cells converge in the orbital tissue, causing associated symptoms. This is followed by a chronic fibrosis stage, which ultimately leads to irreversible restrictive strabismus [24]. Currently, TAO is generally treated with glucocorticoid therapy, immunosuppressant therapy, and retrobulbar radiotherapy; however, a lack of unified and mature treatment plans remains in clinical practice [25]. Currently, increasing evidence suggests that Th17 lymphocytes and regulatory Tregs are crucial to the immune balance of GD and its most common extrathyroidal organ damage-TAO [26,27]. Th17 cells primarily secrete cytokines, including IL-17 (IL-17A), IL-21, and IL-22, and express IL-23 receptor (IL-23R) and chemokine receptor 6. Among them, changes in IL-17 can represent alterations in Th17 cell levels and the occurrence of diseases. IL-23, a key factor for the further expansion and survival of Th17 cells following activation, can generate and maintain the differentiation, maturation, and physiological function of Th17 cells [28,29]. Pan et al. [24] identified that IL-23R plays an essential role as a crucial molecule in the IL-23/IL-23R/PGE₂/EP2 + EP4/IL-23R/IL-17A feedback loop and contributes to Th17 cell differentiation. Furthermore, IL-17A appears to promote the transcription and translation of regulated upon activation, normal Treg expressed and secreted, with the assistance of CD40L by activating the MAPK signalling pathway. Additionally, IL-17A and activated IFN–γ–producing Tregs can synergistically regulate the local inflammatory response in TAO [30]. However, Zake et al. [7] reported that, compared with HT, in the GD group, IL-17 was positively correlated with IL-1β, but not with IL-23 expression, whereas in patients with HT, IL-17 was positively associated with IL-23 and IL-17 with IL-1β expression.

2.2. Role of IL-17 in HT

HT, also referred to as chronic lymphocytic thyroiditis, is a common autoimmune endocrine disease characterized by pathological manifestations, including thyroid epithelial cell destruction, lymphocyte infiltration, tissue fibrosis, and the production of specific antibodies against thyroid antigens [31]. In the later stages of the disease, varying degrees of hypothyroidism are often observed. The exact aetiology of HT has not yet been fully elucidated, but it is generally thought to be closely associated with immune-inflammatory responses influenced by genetics, environmental, and biological factors [6]. Although thyroid hormone replacement therapy effectively corrects hypothyroidism in HT, the underlying immune processes of this progressive autoimmune disease remain incompletely understood, and effective etiological treatments are still lacking. The destructive autoimmune response in HT is traditionally believed to be primarily mediated by type 1 Th1 cells [32]. However, recent studies have indicated that Th17 cells and IL-17 are crucial inflammatory cells and inflammatory mediators involved in the occurrence and development of HT [33]. Th1 cells, by contrast, may accumulate in greater numbers and exert stronger cytotoxic and pro-inflammatory effects, thereby playing a more pathological role in advanced or aggressive forms of HT [34,35]. The levels of Th17 cells and IL-17 in the serum and thyroid tissue of patients with HT are higher than those of healthy people. The increase in serum IL-17 in patients with HT and euthyroid function is more significant than that in patients with hypothyroidism. IL-17 expression is positively correlated with TPOAb and TgAb levels, and negatively associated with thyroid-stimulating hormone levels [36,37]. IL-17 has also been reported to promote Treg proliferation and B lymphocyte differentiation, thereby driving local inflammation and the progression of HT [38]. Additionally, the self-antigen thyroid peroxidase (TPO) has been demonstrated to induce a higher frequency of Th17 cells in HT, suggesting a potential synergistic effect between Th17 cells and TPO [39,40]. The study has also indicated that the expression of glucocorticoid-induced TNF receptor family-related proteins, which are expressed at different levels in CD4+ and CD8+ Tregs and are up-regulated following T-cell activation, increases in patients with HT and is associated with the proportion of Th17 cells [41]. Moreover, Degertekin et al. found that the IL-17 levels in serum were 6.13 pg/mL for euthyroid patients with HT, 4.16 pg/mL for hypothyroid patients with HT, and 4.04 pg/mL for the control group [32]. A study enrolled 216 pregnant women in their second trimester who were negative for TPOAb and TgAb. The researchers measured serum IL-17A levels, thyroid autoantibodies, and thyroid function tests, and further evaluated the ratio of CD4 + IL-17A + Th17 cells. The findings indicated that serum thyroid-stimulating hormone (TSH) levels were inversely associated with both IL-17A levels and the ratio of CD4 + IL-17A + cells. Low levels of IL-17A were correlated with an increased risk of TSH > 2.5 mIU/L and subclinical hypothyroidism; these results suggest that IL-17A plays a crucial role in maintaining normal thyroid function during pregnancy [42]. Some other cytokines produced by macrophages, including IL-β and IL-18, can activate inflammasomes and cell pyroptosis in HT [43,44]. Zake et al. [7] reported that during the progression of HT, thyroid follicles undergo significant atrophy accompanied by epithelial cell destruction, and the expression of IL-17 is markedly increased in thyroid follicular epithelial cells and infiltrating lymphocytes. Given that iodine level plays a crucial role in HT pathogenesis, Li et al. [45] investigated the relationship between iodine exposure and IL-17. Their study found that high iodine levels may promote the polarization of naïve Tregs in the mouse spleen towards Th17 cells by influencing Treg differentiation. In contrast, extremely high iodine levels favoured Th1 polarization while inhibiting the development of Tregs. Previous evidence indicates a crucial role for the gut-thyroid axis in maintaining metabolic and immune homeostasis [46]. In a murine thyroiditis model, Gong et al. revealed that butyrate, a metabolite derived from specific gut bacteria, modulates the Th17/Treg balance through G protein-coupled receptors such as FFAR2 and FFAR3. Excessive iodine intake has been indicated to induce gut microbiota dysbiosis, thereby reducing butyrate production and disrupting this balance. These results suggest that iodine intake affects the metabolic dynamics of the microbiota-gut-thyroid axis [47]. In addition, IL-17 secretion may improve Treg activation and increase MHC class I expression, thereby promoting the progression of papillary thyroid carcinoma in patients with HT [48]. Interestingly, previous clinical studies have indicated that patients with papillary thyroid cancer who have high expression of IL-17A have less lymph node metastasis, indicating that it may have a protective effect in papillary thyroid cancer [48–50]. In summary, these studies suggest that IL-17 and Th17 cells play a crucial role in HT development. The pro-inflammatory effect of IL-17 may drive the thyroid tissue toward specific fibrosis in the early stages of HT, leading to inflammation and stromal fibrosis, whereas Th1 cells are believed to play a pathological role in the later stages of HT [43,45]. Currently, the role of IL-17 and Th17 cells in the disease process of chronic autoimmune thyroiditis requires further study.

3. Interaction between IL-17/Th17 cells and Treg cells

Th17 and Treg cells represent distinct directions of CD4⁺ Treg differentiation, and the two share the TGF-β-mediated signalling pathway [51]. When TGF-β acts alone, activated initial Tregs differentiate into Treg cells. When the body’s immune system is activated, IL-6 and TGF-β act synergistically to induce ROR-γt mRNA expression, driving Treg differentiation into Th17 cells while simultaneously inhibiting Treg cell development [52,53]. Treg inhibits the immune response by secreting immunosuppressive cytokines, including IL-10 and TGF-β [54]. Th17 and Treg cells are both independent and unified in the body’s immune response, jointly maintaining the balance of the body’s immune microenvironment [55]. Once this balance is disrupted, a variety of immune-related diseases can occur [56]. Vitamin D3 plays a dual role in regulating calcium-phosphate balance and regulates bone metabolism, while also modulating immune responses. Deficiency in vitamin D3 has been reported to cause imbalances in Th1/Th17 and Th2, as well as Th17/Treg ratios, which may contribute to the development of AITD [57]. Published research indicates that the inhibitory effect of Vitamin D3 on Th17 cells is mediated through suppression of IL-17 and other cytokines (IL-1, IL-6, and IL-12), and by limiting the differentiation of CD4+ cells into Th17 cells [58]. However, some studies have failed to confirm a direct association between AITD and vitamin D3 deficiency. For instance, two studies that analyzed changes in vitamin D3 levels in patients with AITD found a non-significant correlation between them [59,60]. These contradictory findings still require further detailed evaluation. Li et al. [26] reported that patients with TAO had an increased number of Th17 cells and elevated ROR-γt mRNA expression, whereas this difference was not observed in patients with GD. Besides, peripheral Th17 cells were significantly elevated in patients with severe TAO, but not in those with mild TAO. In contrast, differences in Tregs and their transcription factor Forkhead box protein P3 (FoxP3) between patients with TAO and healthy controls were non-significant compared with those in patients with GD. Therefore, it appears that Th17 cells play a crucial role in TAO development, while Tregs are primarily involved in GD pathogenesis [61]. In mouse experiments, it was found that the FoxP3 of Treg cells can bind to Stat3, inhibiting the Th17 immune response, and Stat3 is considered one of the primary factors for Th17 cell differentiation [62,63]. Treg depletion coIL-17uld induce thyroiditis and anti-Tg antibodies in thyroiditis-resistant IL-17 KO mice [64]. In another study, FoxP3 overexpression was found to inhibit ROR-γt-mediated A mRNA transcription, whereas low expression of FoxP3 was observed to have the opposite effect [65]. In general, impaired FoxP3 expression leads to defects in the regulation of Th17 cell differentiation and an imbalance between Treg and Th17 cells, leading to overactive immune processes and promoting the occurrence and progression of AITD. The therapeutic mechanism of IL-17 effects in pre-clinical studies is indicated in Table 1.

Table 1.

Therapeutic mechanism of IL-17 effects in pre-clinical studies.

Autoimmune thyroid disease	Mechanism or pathway	Reference
Graves’ disease	Retinoid-related orphan receptor gamma t (ROR-γt)	[21]
Graves’ disease	IL-17F/rs763780 polymorphism and IL-17A/rs3819025 SNP	[19]
Graves’ disease	IL-6, CXCL10, and ICAM-1	[18]
Hashimoto’s thyroiditis	T cell proliferation and B lymphocyte differentiation	[38]
Hashimoto’s thyroiditis	Transcription factor ROR-γt and T-bet	[45]
Hashimoto’s thyroiditis	An increase in the natural ligand of glucocorticoid-induced tumor necrosis factor receptor (GITRL) and an impairment in the balance of Th17/Treg	[41]
Hashimoto’s thyroiditis	IL-β and IL-18 produced by macrophages activate inflammasomes	[43]
Graves’ disease and Hashimoto’s thyroiditis	NF-κB signaling pathway	[20]
Autoimmune thyroiditis	miR-326 contributes to AIT by regulating Th17/Treg balance	[53]
Autoimmune thyroiditis	The notch signaling pathway may be involved in thyroid autoimmune injury by promoting the differentiation of Th17 cells	[44]
Thyroid-associated ophthalmopathy	Orbital fibroblasts (OFs) and IL-23/IL-23R/PGE2/EP2 + EP4/IL-23R/IL-17A feedback loop	[24]
Thyroid-associated ophthalmopathy	RANTES expression and CD40-CD40L combination in orbital fibroblasts	[30]
Thyroid-associated ophthalmopathy	CD34+ orbital fibroblasts promote T cell expression of IL-23R and IL-1R, thereby promoting a Th17 cell phenotype via prostaglandin E2-EP2/EP4-cAMP signalling.	[55]
Thyroid-associated ophthalmopathy	Expression of retinoic acid receptor-related orphan receptor T and IL-17A levels	[40]

4. Current IL-17-targeted therapies for AITDs

Several animal-based experiments have investigated the effects of targeted therapies on AITDs, particularly focusing on the IL-17 signalling pathway and TH17 and Treg balance [51,56]. In a pre-clinical study, Pan et al. indicated that subcutaneous administration of the Chinese Patent Medicine JiaYanKangTai alleviated symptoms in Lewis rats with HT, reduced thyroid lobe size, and lowered levels of autoimmune antibodies at a dose of 2.834 g/kg per day for eight weeks [66]. Mechanistically, JiaYanKangTai targets IL-17 signalling and expressions of TRAF6, p-ERK1/2, and TNF-α. Furthermore, Ma et al. [54] reported that Yanghe decoction can enhance autoimmune thyroiditis in rats by regulating the NOD-like receptor family, pyrin domain-containing 3 inflammasome, and immune dysregulation. Moreover, phosphatidylinositol 3-kinase (PI3K) pathway inhibitor LY294002 may be able to mediate Notch signals, regulate the downstream PI3K/AKT/mechanistic target of rapamycin complex 1 pathway, promote Th17 cells to secrete IL-17A, affect Th17 cell differentiation, and play an essential therapeutic role in autoimmune thyroiditis [67].

Previous research has indicated that targeting the IL-17 pathway with monoclonal antibodies—either by neutralizing IL-17 itself or blocking its receptor—represents a viable therapeutic strategy for several immune-mediated diseases [68,69]. Currently, four FDA-approved drugs target the IL-17 pathway: Secukinumab (approved for ankylosing spondylitis, enthesitis-related arthritis, hidradenitis suppurativa, non-radiographic axial spondyloarthritis, plaque psoriasis, and psoriatic arthritis), ixekizumab (for ankylosing spondylitis, non-radiographic axial spondyloarthritis, plaque psoriasis, and psoriatic arthritis), brodalumab (for plaque psoriasis), and bimekizumab (for plaque psoriasis) [70–72]. However, none of these anti-IL-17 therapies have yet been applied to AITD treatment. Further establishment of animal models and deeper investigation into their therapeutic potential for AITD are warranted. In addition, studies have indicated that the Notch signalling pathway influences Th17 cell differentiation by acting on ROR-γt, the lineage-specific transcription factor of Th17 cells. In the AITD mouse model, treatment with DAPT (a γ-secretase inhibitor) blocked the Notch signalling pathway, thereby reducing Th17 cell population, downregulating IL-17A expression, and ultimately alleviating thyroiditis severity [44]. Additionally, other studies have indicated that IGF-1R inhibitor teprotumumab and IL-6 inhibitor tocilizumab exert their beneficial effects in GD and thyroid eye disease by suppressing TSH receptor activation and decreasing the aggregation of orbital fibroblasts, resulting in clinical improvements [73–75]. In summary, current IL-17-targeted therapies and other immunomodulatory inhibitors with potential relevance to AITD are summarized in Table 2. However, few drugs targeting IL-17 have been applied in clinical trials. Given that IL-17 has a small molecular weight and low concentration in the body, numerous challenges must be overcome on the road to clinical drug development [51,76].

Table 2.

Current IL-17-targeted or other inhibitors in therapies for AITDs.

Autoimmune thyroid diseases	Drug	Target	Experimental subjects	Route of administration	Dosage
Hashimoto’s thyroiditis	JiaYanKangTai	IL-17 signaling and expressions of TRAF6, p-ERK1/2, and TNF-α.	Lewis rats	Subcutaneous	2.834 g/kg per day for 8 weeks
Autoimmune thyroiditis	Yanghe decoction	NLRP3 inflammasome and immune dysregulation	Female Sprague-Dawley rats	Oral administration	5 g crude drug/kg or 15 g crude drug/kg of YH from the 7th week to the 12th week
Autoimmune thyroiditis	LY294002	Notch signaling regulates Th17 cells differentiation through PI3K/AKT/mTORC1 pathway	Female C57BL/6 mice	Intraperitoneal injection	The drug intervention time of 25 mg/kg and 50 mg/kg LY294002 was twice a week for 4 weeks
Thyroid-Associated Ophthalmopathy	Teprotumumab (NCT01868997)	IGF-1R/TSH-R axis	Patients in teprotumumab treatment vs placebo treatment	Intravenous administration	Receiving placebo or active teprotumumab administered intravenously once every 3 weeks for 8 infusions
Graves’ orbitopathy	Tocilizumab	Block the interleukin-6 receptor	Patients with active, corticosteroid-resistant, moderate to severe Graves’ orbitopathy	Intravenous administration	Intravenous infusions at a dose of 8mg/kg every 28 days for 4 months and followed up for an additional 6 weeks
Autoimmune thyroiditis	DAPT	Decreasing Th17 cell proportions and downregulating the IL-17A effector cytokine	Female C57BL/6 mice	Intraperitoneal injection	Intraperitoneal injection of DAPT (10 mg/kg) 30 min before the subcutaneous injection of the immunization preparation in mice
Hashimoto’s thyroiditis	Ursolic acid	Modifying gut microbiota composition, attenuating ROS and TNF-α, and controlling Th17/Treg balance	Male SD rats	Intragastrically	100 mg/kg every day for 3 weeks
Autoimmune thyroiditis	Yiqi Jiedu Xiaoying Decoction	Modulating Th17/Treg cell balance, suppressing Th17 cell differentiation, and promoting Treg cell expansion	Female Wistar rats	Intragastrically	34.375 g/kg every day for 8 weeks

5. Discussion

Previous studies have indicated that cellular immune responses mediated by Th1 cells and their cytokines are predominant in HT, whereas humoral immune responses mediated by Th2 cytokines are dominant in GD [26,76]. Th17 cells, a more recently identified subset of CD4-positive Th lymphocytes, exert their effects primarily through secretion of their signature cytokine IL-17A. IL-17 and Th17/Treg immune balance play crucial roles in the pathogenesis of AITD. An increase in the proportion or function of Th17 cells or a decrease in that of Treg may contribute to AITD development [76]. Ongoing clinical trials are needed to evaluate the therapeutic potential of IL-17-targeted interventions as immunotherapies for AITD.

Currently, clinical studies on IL-17 inhibitors are primarily focused on diseases, including psoriasis and ankylosing spondylitis [77,78]. In contrast, IL-17-targeted drugs have demonstrated significant efficacy in some patients; however, 30%–40% of patients experience a poor or no response [77]. Furthermore, IL-17 plays a crucial role in antifungal immunity, and inhibiting IL-17 signalling may elevate the risk of Candida albicans infections of the skin and mucous membranes. Its long-term safety and infection risk need further investigation and verification [79,80]. Furthermore, some patients may exhibit rapid relapse or even rebound following discontinuation of treatment, with inflammation exceeding pre-treatment levels. This may be associated with the disruption of the immune balance caused by the inhibition of the IL-17 pathway, leading to a compensatory release of inflammatory factors upon drug withdrawal [81]. Consequently, patients often require long-term maintenance treatment, which increases both the financial burden and the risk of cumulative adverse reactions [82,83].

Currently, there are few clinical trials targeting autoimmune thyroiditis, and the available basic research and small-scale observational studies have yielded inconsistent findings [51]. The thyroid immune microenvironment is characterized by the synergistic effects of multiple cytokines, including IFN-γ, TNF-α, and IL-6. IL-17 targeted therapy primarily targets the inflammatory response. Simply inhibiting IL-17 may disrupt the immune network, resulting in compensatory activation of other inflammatory pathways and potentially exacerbating thyroid damage [20,43]. Furthermore, the role of IL-17 in thyroid tissue repair remains unclear, and long-term inhibition may impair the repair process. Even if local thyroid inflammation is reduced, it remains challenging to reverse the damage to thyroid tissue function, and most patients still require long-term thyroid hormone replacement therapy [24,31]. As a result, this therapy should only be used as an adjunct and cannot replace traditional hormone replacement therapy. Autoimmune thyroiditis disproportionately affects women, particularly those of childbearing age. However, the effects of IL-17 inhibitors on thyroid function in pregnant and lactating women, as well as on foetal development, remain unclear. The potential risk of endocrine disruption further limits their use in this population [84–86]. In summary, the application of IL-17 targeted therapy in autoimmune thyroiditis remains exploratory, with limitations primarily arising from the complexity of disease mechanisms, insufficient clinical evidence, and the challenges of regulating the immune system. Further fundamental research is needed to clarify the mechanisms of action of IL-17, and targeted clinical trials are necessary to more accurately assess its benefits and risks [43,77].

While IL-17 therapy holds great promise for clinical translation, its application in autoimmune thyroiditis (HT) still faces numerous specific and complex challenges [51]. For instance, clinical phenotypes vary considerably among patients with autoimmune thyroiditis (degree of hypothyroidism, antibody titres, and presence of comorbid autoimmune diseases), and the association between IL-17 expression levels and disease activity in different patients remains unclear. This variability complicates the establishment of consistent inclusion and exclusion criteria for clinical trials [87]. Furthermore, existing studies lack well-defined endpoints for IL-17-targeted therapy [88]. Traditional markers (TPO antibodies and thyroglobulin antibody titres) have weak correlations with the IL-17 pathway and may not adequately reflect treatment-related reduction in inflammation. Although thyroid tissue biopsy can directly assess the severity of inflammation, it is invasive and unsuitable for long-term follow-up [20,89,90]. For example, improvements in thyroid function (TSH and FT4) may lag behind inflammation control and are confounded by hormone replacement therapy, making them inappropriate as standalone efficacy endpoints. Furthermore, the natural course of autoimmune thyroiditis is long and slowly progressive, with some patients remaining subclinical for extended periods. This increases the risk of placebo effects or natural disease fluctuations confounding trial outcomes [91,92]. Besides, existing standard treatments (levothyroxine replacement) only target hypothyroidism and have no overlapping mechanisms of action with IL-17 inhibitors, making it challenging to assess additive or interactive effects of combined therapy [11]. Moreover, thyroid function is closely associated with the hypothalamic-pituitary-adrenal and sex hormone axes. IL-17 inhibitors may influence other hormone levels through immune-endocrine cross-regulation, potentially causing localized thyroid immune imbalance and harmful systemic immunosuppression [15,93]. Currently, IL-17-targeted therapy exhibits limited specificity for thyroid tissue, and uncertainties remain regarding optimal dosage and treatment duration. In certain populations, such as women of childbearing age, IL-17 plays a crucial role in immune tolerance during pregnancy, and its inhibition may affect pregnancy outcomes or foetal thyroid development [15,94]. These risk requires rigorous evaluation in clinical trials, but relevant data are still lacking. In summary, the clinical translation of IL-17-targeted therapy for autoimmune thyroiditis faces several major challenges: Overcoming trial design bottlenecks caused by disease heterogeneity, defining safety margins under immune-endocrine interactions, and improving targeted drug delivery to thyroid tissue [51,94]. Future efforts should integrate precision medicine approaches (IL-17 pathway activity markers) to optimize patient stratification, develop localized thyroid drug delivery methods (ultrasound-guided local injection), and conduct long-term, real-world studies to facilitate the transition from basic research to clinical application.

Funding Statement

The research was supported by Zhejiang Provincial Health Commission, General Project of Zhejiang Medical and Health Science and Technology Project (2024KY1712), and Shaoxing Basic Public Welfare Research Program (2024A14009).

Ethics approval

Not applicable.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.