1 Introduction

Thyroid cancer is the most common malignant endocrine tumor and can be classified into the four main pathological types: papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC). PTC and FTC are more prevalent, exhibiting a higher degree of differentiation and less aggressive. In contrast, MTC and ATC have more aggressive than other thyroid cancers, resulting in a poorer patient prognosis. Some studies have confirmed PCD as a crucial mechanism in thyroid cancer initiation and progression, with significant implications for long-term prognosis [1]. As a common regulatory mechanism in cell death, PCD modulates the spontaneous death of damaged cells when stimulated by internal or external environmental factors by initiating “suicide protection”. Here, we provide an overview of the pivotal role of PCD in the pathogenesis and development of thyroid cancer through six common pathways: apoptosis, pyroptosis, necroptosis, autophagy, ferroptosis, and cuprotosis (a newly reported mechanism).

2 Apoptosis

Apoptosis is a self-initiated proactive process of PCD regulated by specific genes or pathways. Traditionally, apoptosis involves caspase (cysteine-dependent aspartate-directed protease)-mediated proteolysis and concurrent DNA cleavage through the activation of signal transduction pathways [2]. In recent years, there has been increasing evidence regarding the correlation between apoptosis and thyroid carcinogenesis. For example, as a central endocrine regulator, thyroid hormones reportedly promote thyroid carcinogenesis by inducing tumor cell proliferation, activating apoptosis-downstream pathways such as the mitogen-activated protein kinase (MAPK) pathway, and downregulating proapoptotic markers including caspase-3 [3]. Additionally, Chu et al. confirmed that knockdown of the intracellular transcription factor forkhead box P3 (FOXP3) inhibits cancer cell proliferation and metastasis, and induces apoptosis in thyroid cancer cells. This suggests that FOXP3 upregulation can lead to a decrease of apoptosis in thyroid cancer [4]. Alantolactone, extracted from traditional Chinese herbs, has anti-inflammatory, antibacterial, and antitumor properties. To investigate potential against ATC, Hu et al. verified that alantolactone triggers mitochondria-dependent activation of cysteine asparaginase by mediating reactive oxygen species (ROS) generation and decreasing the Bcl-2/Bax ratio. With the decrease in mitochondrial membrane potential and an increase in cytochrome c release, caspases-9 and −3 can be cleaved—this induces apoptosis and gasdermin (GSDM) E (GSDME)–dependent pyroptosis in thyroid cancer cells. These mechanisms in thyroid cancer cells show clear characteristics of immunogenic cell death, suggesting that alantolactone may also play an important role in the immune response of thyroid cancer cells. Therefore, it is speculated that targeted therapy with alantolactone and immunotherapy may more efficiently inhibit the progression of poorly differentiated thyroid cancers [5]. (Fig. 1).

Fig. 1
figure 1

The apoptosis signaling pathway. Alantolactone mediates the generation of reactive oxygen species (ROS) and decreases the Bcl-2/Bax ratio, which leads to caspase-9 and −3 cleavage by decreasing the mitochondrial membrane potential and increasing cytochrome c release, ultimately inducing apoptosis in thyroid cancer cells. Thyroid hormones inhibit apoptosis in thyroid cancer cells through activation of the MAPK (mitogen-activated protein kinase) signaling pathway. FOXP3 inhibition promotes apoptosis in thyroid cancer cells and suppresses thyroid carcinogenesis

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3 Pyroptosis

Pyroptosis is a proinflammatory form of PCD characterized by pyroptosome-mediated caspase activation. This activation leads to the cleavage of GSDM family proteins, which in turn induces the formation of cell membrane pores and the release of active proinflammatory factors such as interleukin (IL)−1 and IL-18 [6]. Recent studies have increasingly provided evidence of the relationship between pyroptosis and thyroid carcinogenesis. Many studies have identified specific genes or molecules associated with pyroptosis in thyroid cancer, focusing on caspase- and GSDM-medicated signaling pathways. For example, apatinib, a targeted drug with antiangiogenic effects, combined with bee venom, reportedly induces pyroptosis in ATC cancer cells via the caspase-1-GSDMD and caspase-3-GSDME axes. Furthermore, apatinib induces autophagy or apoptosis in ATC cancer cells by modulating the PI3K/AKT/mTOR1 signaling pathway. Moreover, chloroquine, an autophagy inhibitor, promotes apatinib-induced apoptosis in ATC cancer cells, implying that chloroquine can elicit additional tumor suppression. Therefore, chloroquine may augment the anti-ATC effects of apatinib [7]. This finding may provide a new avenue for targeted therapy for ATC. Our understanding of pyroptosis remains unclear; hence, identifying differentially expressed genes in pyroptosis may help improve the potential of precise targeted therapy for poorly differentiated thyroid cancer. (Fig. 2).

Fig. 2
figure 2

The pyroptosis signaling pathway. Apatinib induces pyroptosis in thyroid cancer cells through the caspase-1–gasdermin (GSDM) D and caspase-3–GSDME axes. Additionally, apatinib also triggers autophagy and apoptosis by inhibiting the PI3K/Akt/mTOR signaling pathway

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4 Necroptosis

Necroptosis is a form of PCD characterized by necrotic cellular morphology, initiated through the serine/threonine kinase 1 and 3 (RIP1/RIP3) signaling pathway [8,9,10]. Tumor necrosis factor (TNF)-α binds to TNFR1 at the cell membrane, forming the TNF receptor-associated death domain (TRADD) complex. This complex recruits downstream molecules to form complex I, which regulates RIPK1, ultimately inducing necroptosis [11, 12]. Recent studies have reported that necroptosis plays a significant role in thyroid carcinogenesis. For example, Nehs et al. found that increasing radiation doses can induce necroptosis in thyroid cancer cell lines. This effect can be enhanced in the presence of the necrosis inhibitor Necrostatin-1 (Nec-1) or the apoptosis inhibitor zVAD-FMK (zVAD). This suggests that necroptosis may enhance the effectiveness of iodine-131 therapy in patients with advanced thyroid cancer [13]. Current evidence on the relationship between necroptosis and thyroid carcinogenesis is inadequate. Thus, differentially expressed molecules need to be identified. Furthermore, studies are needed to investigate whether these molecules can synergistically regulate necroptosis and other forms of PCD including apoptosis, for more precise treatment of patients with thyroid cancer with a poor prognosis. (Fig. 3).

Fig. 3
figure 3

The necroptosis signaling pathway. Tumor necrosis factor (TNF)–α binds to TNFR1 to form the TNF receptor–associated death domain (TRADD) complex, which recruits downstream molecules leading to the assembly of complex I. Thereafter, complex I triggers necroptosis by regulating RIPK1. The presence of necroptosis inhibitor Necrostatin-1 (Nec-1) or apoptosis inhibitor zVAD-FMK in thyroid cancer cells can enhance the effect of necroptosis. This effect can improve the therapeutic efficacy of iodine-131 in advanced thyroid cancer

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5 Autophagy

Autophagy is a crucial cellular process. To maintain cellular health and homeostasis, normal cells degrade and eliminate damaged or unnecessary components to combat inflammation, infection, or metabolic disorder [14]. The basic process involves the detachment of unattached ribosome double membranes from the rough endoplasmic reticulum, followed by wrapping up of cellular components including the protoplasm. These components form autophagosomes, which subsequently fuse with lysosomes. Thereafter, the encapsulated substances are degraded to fulfill the metabolic requirement of cells and facilitate the renewal of specific organelles. This process helps maintain cellular homeostasis and provides substrates or raw materials for diverse biochemical reactions [15]. Recent studies have identified differentially expressed molecules associated with autophagy during thyroid carcinogenesis. For example, Qin et al. suggested that ATG3 and ATG5 can promote autophagy in thyroid cancer cells via the RBM47/SNHG5/FOXO3 axis, indicating that ATG3 and ATG5 play a significant role in inhibiting cancer cell proliferation in PTC [16]. Furthermore, high mobility group box 1 (HMGB1) is a positive regulator of autophagy [17]. On investigating HMBG1’s role in thyroid cancer, Chai et al. found that knockdown of HMGB1 not only inhibited autophagy but also promoted iodine uptake in the sodium/iodine symporter (NIS) in Hank’s Balanced Salt Solution (HBSS)-treated thyroid cancer cells, implying that HMGB1 potentially promotes tumorigenic factors, and offering an alternative to iodine-131 radiotherapy for patients with thyroid cancer [18]. BRAFV600E, the most common oncogenic mutation in thyroid cancer, induces autophagy under the influence of the specific inhibitor PLX4720. Moreover, Jimenez et al. found that the knockdown of BRAFV600E can activate the LKB1/AMPK/mTOR signaling pathway, which ultimately induced apoptosis. This implies that BRAFV600E may represent a critical association for the interplay between autophagy and apoptosis in thyroid cancer cells, making it a potentially valuable target for treating thyroid cancers with a poor prognosis [19]. Regarding drug therapy, both modern and traditional medicines have demonstrated their antitumor effects through modulation of the autophagy signaling pathway. For instance, aloperine, an alkaloid with diverse antitumor properties, has recently been discovered to promote caspase-dependent autophagy through the Akt signaling pathway. Moreover, aloperine induces autophagy by synergistically suppressing the PI3K/Akt/mTOR signaling pathway upon rapamycin supplementation during thyroid carcinogenesis. Thus, aloperine may impede thyroid cancer progression in patients with a poor prognosis [20]. Astragalus, a Chinese herbal medicine abundant in Calycosin, promotes apoptosis and autophagy in thyroid cancer cells through the Sestrin2/AMPK/mTOR pathway, thus suppressing cancer cell migration and invasion in PTC [21]. During targeted therapy, anlotinib, similar to apatinib, exhibits antiangiogenic effects. In cases of patients with thyroid cancer with a poor prognosis, anlotinib induced aberrant aggregation of spindle bodies, G2/M phase arrest, and TP53 activation in thyroid cancer cells [22]. Furthermore, autophagy plays a dual role in thyroid cancer progression by not only impeding the growth of thyroid cancer cells by degrading oncogenic proteins, but also causing the degradation of normal thyroid cells. Energy generated from the degradation processes may be recycled by thyroid cancer cells, thereby promoting thyroid cancer progression [23, 24]. Recent studies on the association between autophagy and thyroid carcinogenesis are increasingly reliable. Understanding the mechanism regulating autophagy is crucial for improving targeted therapy. The precise targeted therapy can help in effectively treating thyroid cancer in patients with a poor prognosis, minimize the occurrence of unnecessary side effects, and enhance the overall survival of patients with thyroid cancer. (Fig. 4).

Fig. 4
figure 4

The autophagy signaling pathway. Astragalus alleviates thyroid cancer progression through the Sestrin2/AMPK/mTOR signaling pathway to promote autophagy and induce apoptosis. ATG3 and ATG5 promote autophagy and inhibit thyroid cancer cell proliferation via the RBM47/SNHG5/FOXO3 axis. Aloperine promotes caspase-dependent autophagy through the Akt signaling pathway and synergistically inhibits the PI3K/Akt/mTOR signaling pathway in combination with rapamycin to induce autophagy. BRAFV600E induces autophagy in the presence of the specific inhibitor PLX4720. Additionally, knockdown of BRAFV600E can modulate the LKB1/AMPK/mTOR signaling pathway, thereby inducing apoptosis

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6 Ferroptosis

Ferroptosis is a novel form of PCD characterized by iron-dependent lipid peroxidation-induced mitochondrial damage. This primarily occurs through the Fenton reaction between intracellular ferrous ions and unsaturated fatty acids on the cell membrane, leading to excessive ROS generation. When the cellular antioxidant capacity is overwhelmed, ROS accumulation on membrane lipids will increase. Oxidative stress can result in cell death, and ROS accumulation can also result from a deficiency in the membrane lipid repair enzyme glutathione peroxidase 4 (GPX4) [25, 26]. Recent studies have shown a significant association between ferroptosis and thyroid cancer progression. For instance, to explore the role of circKIF4A in PTC, Chen et al. identified circKIF4A as a ferroptosis regulator. They found that circKIF4A upregulates GPX4 and suppresses lipid peroxidation via the circKIF4A/miR-1231/GPX4 axis, thus inhibiting ferroptosis and contributing to thyroid carcinogenesis. This finding suggests that targeting circKIF4A may be a promising approach for treating thyroid cancer in patients with a poor prognosis [27]. Moreover, some studies have shown that circ0067934 downregulation can induce ferroptosis in thyroid cancer cells and inhibit their proliferation simultaneously. Conversely, circ0067934 upregulation indicates a poor prognosis for thyroid cancer [28, 29]. As a key component of the ferroptosis mechanism, SLC7A11 knockdown reportedly reduced E26 transformation-specific variant 4 (ETV4) levels, leading to ferroptosis in thyroid cancer cells. This suggests that ETV4 may be a potential therapeutic target for thyroid cancer [30]. Furthermore, diaryl ether derivative, 16 can induce ferroptosis in thyroid cancer cells by suppressing GPX4, implying that diaryl ether derivative, 16 may help improve the effectiveness of targeted therapy for drug-resistant thyroid cancer [31]. Current studies on ferroptosis for thyroid cancers remain partial. Therefore, it is critical for therapies to target steadily expressed genes that are associated with ferroptosis in thyroid cancer cells that are at different levels of differentiation. (Fig. 5).

Fig. 5
figure 5

The ferroptosis signaling pathway. E26 transformation-specific variant 4 (ETV4) downregulation can lead to SLC7A11 downregulation and increase glutathione levels. This process ultimately induces ferroptosis in thyroid cancer cells. Diaryl ether derivative, 16 induces ferroptosis in thyroid cancer cells by suppressing glutathione peroxidase 4 (GPX4), ultimately suppressing thyroid carcinogenesis. CircKIF4A enhances GPX4 activity and suppresses lipid peroxidation through the circKIF4A/miR-1231/GPX4 axis, thereby inhibiting ferroptosis and promoting thyroid carcinogenesis

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7 Cuprotosis

Cuprotosis is a newly discovered form of PCD that occurs during mitochondrial respiration and affects the tricarboxylic acid (TCA) cycle. The aggregation of reduced copper ions bound to lipoylated proteins in this cycle leads to the downregulation of iron-sulfur cluster proteins, causing proteotoxic stress and eventually resulting in cell death. Few studies have identified several genes that promote or inhibit cuprotosis. For instance, FDX1, LIAS, LIPT1, DLD, DLAT, PDHA1, and PDHB promote cuprotosis, while MTF1, GLS, and CDKN2A inhibit cuprotosis. Additionally, ATP7B and SLC31A1 are involved in copper transport proteins [32]. Ferredoxin 1 (FDX1), identified as a crucial cuprotosis regulator, is associated with thyroid carcinogenesis. This finding also provides valuable insights for thyroid carcinogenesis [33]. Elesclomol, a copper ion carrier, is also associated with thyroid carcinogenesis. Moreover, elesclomol reportedly downregulated FDX1, strengthened the effect of cuprotosis in thyroid cancer cells, and inhibited thyroid carcinogenesis [34]. Du et al. found that models involving significantly different expression levels of cuproptosis-related genes (CRGs) in thyroid cancer include FDX1, BUB1, and RPL3. By comparison, they suggested that CRGs might be crucial regulators of cuproptosis in the pathogenesis of thyroid cancer through the ataxia-telangiectasia mutated (ATM) signaling pathway [35]. Based on the available evidence, it is reasonable to speculate that cuprotosis is closely associated with thyroid cancer. However, studies are needed to investigate the mechanisms underlying cuprotosis pathways and identify effective targets for new diagnostic and therapeutic strategies for patients with a poor prognosis. (Fig. 6).

Fig. 6
figure 6

The cuprotosis signaling pathway. Elesclomol inhibits thyroid carcinogenesis by downregulating ferredoxin 1 (FDX1) and strengthening the effect of cuprotosis in thyroid cancer cells. Cuproptosis-related gene (CRG) models (involving FDX1, BUB1, and RPL3) may regulate cuproptosis through the ataxia-telangiectasia mutated (ATM) signaling pathway in thyroid cancer cells

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8 Conclusions

Thyroid cancer is the most prevalent endocrine malignancy. The incidence of poor prognosis subtypes, including MTC, ATC, and aggressive variants of PTC, has been steadily increasing over the years [36]. This paper provides a review of the relationship between PCD and thyroid carcinogenesis, aiming to enhance the efficacy of targeted therapy for thyroid cancer in patients with a poor prognosis. These findings can lay the foundation for the development of targeted therapeutic strategies in the future. Moreover, the identification of shared or upregulated targets in managing drug-resistant thyroid cancer, poorly differentiated thyroid cancer, and iodine-refractory thyroid cancer will be a key focus of future therapeutic research.