Michelle Carnazza, Nan Yang, Raj K. Tiwari, Jan Geliebter, Xiu-Min Li
Thyroid cancer (TC) represents the most prevalent endocrine malignancy, with papillary thyroid cancer (PTC) comprising approximately 80% of cases and accounting for the majority of annual incidence and mortality. PTC is generally confined to the thyroid gland and demonstrates an excellent prognosis after surgery, with a five-year survival rate exceeding 90%. Nevertheless, recurrence can occur, and the ten-year survival rate for the advanced PTC is below 50%. Even after effective successful surgical intervention, many still require ongoing surveillance, additional treatment, and lifelong thyroid hormone replacement, while facing the potential adverse effects such as hormone fluctuations, surgical complications, and sequelae of radioactive iodine exposure. Naturally occurring compounds have demonstrated anti-cancer properties and hence the potential to be used as therapeutic options, impacting the same drivers and pathways involved in the tumorigenesis of thyroid cancer. This narrative review focuses on the natural compounds' convergence on molecular nodes of PI3K/Akt, MAPK, and JAK/STAT to overcome therapeutic resistance and restore apoptosis, highlighting their potential in advanced and recurrent PTC.