Abstract

Lenvatinib resistance is a major clinical obstacle in the treatment of radioiodine-refractory papillary thyroid cancer (PTC). Clarification of the molecular mechanisms of this resistance is of utmost importance to devise effective therapeutic strategies. We investigated the role of Keratin 15 (KRT15) in lenvatinib resistance through comprehensive in vitro and in vivo studies. Tumor and normal thyroid tissues were analyzed for KRT15 expression and correlation with patient survival. Metabolic profiling was performed to investigate KRT15-dependent alterations in lipid metabolism, namely fatty acid oxidation (FAO). Mechanistic investigations explored the interaction between KRT15, Keratin 81 (KRT81), and Diacylglycerol Kinase B (DGKB). The therapeutic potential of targeting this pathway was evaluated using shRNA-mediated knockdown and pharmacological inhibition. KRT15 overexpression was associated with unfavorable clinical prognosis in thyroid cancer patients. We identified that KRT15 interacts with KRT81 to constitute a regulatory complex, which induces DGKB upregulation. The KRT15-KRT81-DGKB axis controls metabolic reprogramming by upregulating key FAO enzymes (CPT1A and ACOX1), resulting in increased cellular energetics and survival against therapeutic stress. Inhibition of this pathway successfully restored lenvatinib sensitivity in resistant cells. This study illustrates a novel mechanism of cytoskeletal proteins involvement in metabolic adaptation of drug-resistant thyroid cancer cells. The KRT15-KRT81-DGKB pathway is a promising therapeutic target, particularly in combination with lenvatinib, for refractory thyroid cancer patients.