Mechanistic insights into ferroptosis in thyroid cancer and its therapeutic implications

Thyroid cancer (TC), the most common endocrine malignancy, presents significant clinical challenges due to the risk of recurrence, metastasis, and treatment resistance, particularly in advanced cases. Driven by lipid peroxidation, ferroptosis is an iron-dependent, regulated cell death pathway increasingly implicated in cancer biology. This review comprehensively summarizes the mechanistic basis of ferroptosis, encompassing iron metabolism, amino acid regulation, lipid peroxidation, and key regulators such as p53, Nrf2, heat shock proteins and its specific implications in thyroid cancer. This study delineates the contribution of both coding and non-coding ferroptosis-related genes as critical modulators of thyroid cancer progression, thereby influencing patient prognosis. The interplay between ferroptosis and the tumor immune microenvironment is also discussed, emphasizing how immune cells like CD8( +)T cells and macrophages influence and respond to ferroptotic signals. Furthermore, we explore the therapeutic potential of targeting ferroptosis using both natural compounds and synthetic agents, which have shown promise in inducing ferroptosis and suppressing tumor growth in preclinical models. Notably, emerging evidence suggests that activating ferroptosis may help overcome radioiodine resistance and improve survival outcomes, particularly in aggressive subtypes such as anaplastic thyroid cancer (ATC). Therefore, the exploitation of ferroptosis offers a promising avenue to address therapeutic resistance and improve prognosis in thyroid cancer, which merits further clinical investigation.