Signaling pathways and targeted therapy in high‑risk refractory thyroid cancer: From bench to bedside (Review).

Thyroid cancer is the most common endocrine malignancy worldwide, with its incidence increasing markedly over the past several decades, while mortality trends have shown complex patterns. High‑risk refractory thyroid cancers (including radioactive iodine‑refractory differentiated thyroid cancer, poorly differentiated thyroid cancer, anaplastic thyroid carcinoma, progressive medullary thyroid carcinoma and locally advanced disease) pose major challenges in clinical management. The present review systematically reviewed recent epidemiological trends in thyroid cancer and provided an in‑depth exploration of the molecular regulatory mechanisms of key signaling pathways, including MAPK, PI3K/AKT, Janus kinase/STAT, WNT/β‑catenin and NF‑κB, along with their roles in the pathogenesis and progression of thyroid cancer. Based on this, the latest clinical research advances in targeted therapies for high‑risk, refractory thyroid cancer are elaborated on, covering multikinase inhibitors, B‑Raf proto‑oncogene, serine/threonine kinase/mitogen‑activated protein kinase kinase inhibitors, immunotherapy combinations, innovative targeted strategies and redifferentiation approaches. Finally, future directions are discussed based on the 'total treatment' paradigm and strategies to overcome drug resistance, aiming to provide a systematic reference for basic research and clinical translation in thyroid cancer.