Uncovering the connection between obesity and thyroid cancer: the therapeutic potential of adiponectin receptor agonist in the AdipoR2-ULK axis

Adiponectin, a unique adipose-derived factor, is significantly downregulated in obesity, making it a crucial target for tumor-related metabolic research. AdipoRon is a novel adiponectin receptor agonist with the advantages of a small molecular weight, high stability and a long half-life. By screening the cervical adipose tissue of papillary thyroid carcinoma (PTC) patients with adipokine antibody array, we found that adiponectin was a potential correlation factor between obesity and PTC progression. AdipoRon has oral activity and is easily absorbed and delivered to target tissues. The effects of AdipoRon on thyroid cancer have not been reported. In this study, we identified adiponectin receptor 1 (AdipoR1) and AdipoR2 on the surface of thyroid cancer cell lines. AdipoRon inhibited the proliferation and migration of thyroid cancer cells, limited energy metabolism in thyroid cancer cells, promoted differentiation of thyroid cancer cells, and induced autophagy and apoptosis. Mechanistic studies revealed that AdipoRon inhibited p-mTOR ^Ser2448 and p-p70S6K ^Thr389, and activated ULK1 and p-ULK1. ULK1 knockdown suppressed the effect of AdipoRon on LC3BII/I protein and lysosomes. AdipoR2 knockdown reduced AdipoRon-induced autophagy in thyroid cancer cells. This study is the first to demonstrate the role of AdipoRon in PTC. Our findings illustrate a previously unknown function and mechanism of the AdipoRon-AdipoR2-ULK/p-ULK1 axis in PTC and lay the foundation for clinical translation of AdipoRon to PTC. Targeting the AdipoRon-AdipoR2-ULK/p-ULK1 axis may represent a new therapeutic strategy for PTC.