The evolving process of ferroptosis in thyroid cancer: Novel mechanisms and opportunities

Abstract

Thyroid cancer (TC) is a prevalent endocrine malignancy, with a significant increase in incidence worldwide. Ferroptosis is a novel form of programmed cell death, primarily caused by iron overload and reactive oxygen species (ROS)-dependent accumulation of lipid peroxides. The main manifestations of cellular ferroptosis are rupture of the outer membrane, crumpling of the mitochondria and shrinkage or disappearance of the mitochondrial cristae, thus leading to cell death. Ferroptosis is an important phenomenon in tumour progression, with crosstalk with tumour-associated signalling pathways profoundly affecting tumour progression, immune effects and treatment outcomes. The functions and mechanisms of ferroptosis in TC have also attracted increasing attention, mainly in terms of influencing tumour proliferation, invasion, migration, immune response, therapeutic susceptibility and genetic susceptibility. However, at present, the tumour biology of the morphological, biological and mechanism pathways of ferroptosis is much less deep in TC than in other malignancies. Hence, in this review, we highlighted the emerging role of ferroptosis in TC progression, including the novel mechanisms and potential opportunities for diagnosis and treatment, as well as discussed the limitations and prospects. Ferroptosis-based diagnostic and therapeutic strategies can potentially provide complementary management of TCs.

Keywords: ferroptosis; ferroptosis‐related gene; ferroptosis‐targeted therapy; lipid peroxidation; thyroid cancer.

FIGURE 1

Classification and immune microenvironment of thyroid carcinoma. Based on the origins and extent of differentiation, thyroid cancer could be classified as papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC) and anaplastic thyroid cancer (ATC). The immune microenvironment in thyroid carcinoma is a complex and dynamic system, where host cells coexist with tumour cells and act through mutual interactions to promote or inhibit tumour progression. This interaction involves the secretion of various cytokines, chemokines and antibodies from B cells. Additionally, immune cells could also directly contact tumour cells to exert anti‐tumour effects.

FIGURE 2

Mechanisms of ferroptosis. Fe3⁺ bound to transferrin enters the cell via the transferrin receptor and is then reduced to Fe2⁺ by STEAP3 in the lysosome. Fe2⁺ could enter the cytoplasm through DGT1, together with Fe2⁺ from degraded heme and Fe2⁺ released by NCOA4‐mediated ferritinophagy to form LIP. Extracellular Fe2⁺ could also penetrate directly into the cell via DGT1 located on the membrane and participate in the formation of LIP. Fe2⁺ within the LIP has three main endings: Passing out of the cell via ferroportin, being stored by binding to ferritin, and generating ROS by Fenton reaction. ROS generated by the Fenton reaction along with other metabolic processes could facilitate the initiation of lipid peroxidation, and ultimately, cause ferroptosis together with ALOXs. System Xc‐ and GPX4 are the main components that inhibit lipid peroxidation, while AIFM2‐CoQ10, GCH‐1‐BH4 and DHODH‐CoQH2 also prevent the occurrence of lipid peroxidation in the cell.

FIGURE 3

The role and mechanisms of ferroptosis in remodelling TC progression. M6A modification: ALKBH5 could downregulate the m6A level of TIAM1, thereby promoting ferroptosis through the TIAM1/Nrf‐2/HO‐1 axis. FTO promoted the downregulation of m6A in SLC7A11 and inhibited SLC7A11 function, facilitating ferroptosis in TC cells. NcRNAs regulation: The lncRNA CERS6‐AS1 could inhibit ferroptosis via the miR‐417‐5p/LASP1 axis, while circ_KIF4A suppressed ferroptosis via miR‐1231/GPX4 axis. Circ_0067934 could enhance the expression of SLC7A11 via sponge‐binding with miR‐545‐3p, thus preventing ferroptosis and promoting the proliferation of TC cells. GPX4: GPX4 is an essential factor in preventing ferroptosis, which could reduce intracellular ROS levels, lipid peroxidation products, and DNA damage, resulting in promoted TC cell proliferation and migration. ETV4: ETV4 regulates the expression of chemokines, and it also inhibits ferroptosis in tumour cells via SLC7A11. TFR1: TFR1 is a pivotal component of Fe intake, and ATC cells could enhance their resistance to ferroptosis by down‐regulating TFR1. SIRT6: USP10 could suppress erastin‐induced ferroptosis by SIRT6‐induced GPX4 promotion. Meanwhile, SIRT6 could in turn enhance NCOA4‐mediated ferritinophagy, increasing the levels of LIP and enhancing ferroptosis.