Ferroptosis in Anaplastic Thyroid Cancer: Molecular Mechanisms, Preclinical Evidence, and Therapeutic Prospects

TL;DR

This paper explores how triggering ferroptosis, a type of cell death, could offer new treatment options for aggressive anaplastic thyroid cancer.

Contribution

The paper identifies genetic regulators and combination therapies that modulate ferroptosis in anaplastic thyroid cancer.

Findings

ATC cells are vulnerable to ferroptosis due to disrupted iron and lipid metabolism.

Genetic regulators like SIRT6 and GPR34–USP8 influence ferroptosis sensitivity in ATC.

Combining BRAF inhibitors with GPX4 blockade improves ATC suppression.

Abstract

What are the main findings?
ATC exhibits ferroptosis vulnerability due to dysregulation of iron and lipid metabolism.Genetic regulators, including SIRT6, EIF3H–β-catenin, and GPR34–USP8, shape ferroptosis sensitivity.RON signaling links glycolysis to ferroptosis resistance, offering a new therapeutic target.

ATC exhibits ferroptosis vulnerability due to dysregulation of iron and lipid metabolism.

Genetic regulators, including SIRT6, EIF3H–β-catenin, and GPR34–USP8, shape ferroptosis sensitivity.

RON signaling links glycolysis to ferroptosis resistance, offering a new therapeutic target.

What are the implications of the main findings?
Natural compounds such as vitamin C, neferine, curcumin, and shikonin induce ferroptosis in ATC.Anlotinib triggers ferroptosis via ROS and ER stress, amplified by autophagy blockade.Combination regimens, including BRAF inhibitors with GPX4 blockade or isobavachalcone plus doxorubicin, enhance ATC suppression.

Natural compounds such as vitamin C, neferine, curcumin, and shikonin induce ferroptosis in ATC.

Anlotinib triggers ferroptosis via ROS and ER stress, amplified by autophagy blockade.

Combination regimens, including BRAF inhibitors with GPX4 blockade or isobavachalcone plus doxorubicin, enhance ATC suppression.

Anaplastic thyroid cancer (ATC) is among the most lethal human malignancies, characterized by rapid progression, therapeutic resistance, and a median survival of less than one year. Conventional therapies, including surgery, radiotherapy, and chemotherapy, have limited effect, and targeted or immune-based treatments provide only transient benefit. Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has recently emerged as a therapeutic vulnerability in ATC. This review synthesizes current evidence on ferroptosis biology, preclinical validation, and therapeutic implications in ATC. Genomic alterations such as TP53, BRAFV600E, RAS, and PIK3CA converge on redox imbalance and metabolic rewiring, rendering ATC cells dependent on antioxidant defenses. Dysregulated iron homeostasis through ferritinophagy and HO-1 activity, together with lipid remodeling via ACSL4 and LPCAT3, further sensitizes ATC to ferroptosis. Preclinical studies show that pharmacological inducers, including vitamin C, tenacissoside H, neferine, curcumin, and shikonin, as well as targeted agents such as dabrafenib and anlotinib, can trigger or synergize with ferroptosis. Genetic regulators, including SIRT6, the GPR34–USP8 axis, and the EIF3H–β-catenin pathway, modulate ferroptosis sensitivity, while RON receptor signaling links glycolysis to ferroptosis resistance. Combination regimens provide further translational potential. Nanoplatforms also offer innovative delivery strategies. Therapeutic approaches include initiating ferroptosis through iron and PUFA enrichment, disabling defenses such as GPX4 and Nrf2, and integrating ferroptosis inducers with existing modalities. Although systemic toxicity and resistance remain obstacles, biomarker-driven selection and drug repurposing offer promise. Ferroptosis represents a mechanistically distinct and clinically exploitable pathway for ATC.

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