Transcriptome analysis of KRT15 knockdown in lenvatinib-resistant papillary thyroid carcinoma cells

Lenvatinib resistance is a major clinical obstacle in the treatment of radioiodine-refractory papillary thyroid cancer (PTC), and clarifying its molecular mechanisms is crucial for developing effective therapeutic strategies. In this study, we identify Keratin 15 (KRT15) as a key driver of this resistance. We found that KRT15 overexpression is associated with an unfavorable clinical prognosis in PTC patients. Mechanistically, KRT15 interacts with Keratin 81 (KRT81) to form a regulatory complex that upregulates Diacylglycerol Kinase B (DGKB). This KRT15-KRT81-DGKB axis drives metabolic reprogramming by increasing the expression of key fatty acid oxidation (FAO) enzymes, such as CPT1A and ACOX1, which enhances cellular energetics and promotes survival under therapeutic stress. Consequently, inhibition of this pathway successfully resensitizes resistant cells to lenvatinib. Taken together, our study reveals a novel mechanism where cytoskeletal proteins mediate metabolic adaptation in drug-resistant PTC cells, identifying the KRT15-KRT81-DGKB pathway as a promising therapeutic target to overcome lenvatinib resistance in refractory PTC patients.