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The KRT15 and KRT81 complex promotes lenvatinib resistance in thyroid cancer by upregulating DGKB mediated lipid

Yunjun Wang1,2, Yu Zhang1,2, Dan Zhao1,2

  • 1Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Scientific Reports
|April 16, 2026
PubMed

Insights

Keratin 15 (KRT15) promotes lenvatinib resistance in papillary thyroid cancer by altering lipid metabolism. Targeting the KRT15-KRT81-DGKB pathway can restore drug sensitivity, offering a new therapeutic strategy for refractory thyroid cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolism

Background:

  • Lenvatinib resistance is a significant challenge in treating radioiodine-refractory papillary thyroid cancer (PTC).
  • Understanding the molecular mechanisms driving this resistance is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the role of Keratin 15 (KRT15) in lenvatinib resistance in PTC.
  • To elucidate the molecular pathway involving KRT15 in metabolic adaptation and drug resistance.

Main Methods:

  • Analysis of KRT15 expression in tumor and normal thyroid tissues.
  • In vitro and in vivo studies, including metabolic profiling (fatty acid oxidation - FAO).
  • Investigation of KRT15, KRT81, and DGKB interactions; shRNA knockdown and pharmacological inhibition.

Main Results:

  • KRT15 overexpression correlated with poor prognosis in thyroid cancer patients.
  • KRT15, through interaction with KRT81, upregulates DGKB, enhancing FAO enzymes (CPT1A, ACOX1).
  • This KRT15-KRT81-DGKB axis promotes metabolic reprogramming, increasing cellular energetics and survival against lenvatinib.

Conclusions:

  • The KRT15-KRT81-DGKB pathway is a novel mechanism contributing to lenvatinib resistance in PTC via metabolic adaptation.
  • Targeting this pathway, particularly in combination with lenvatinib, shows therapeutic potential for refractory thyroid cancer.
Keywords:
DGKBKRT15KRT81Lenvatinib resistanceLipid metabolismThyroid cancer

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