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  3. Activation of YBX1 and JAK2/STAT3 pathways by RIOK1 increases lenvatinib resistance in hepatocellular carcinoma cells

Activation of YBX1 and JAK2/STAT3 pathways by RIOK1 increases lenvatinib resistance in hepatocellular carcinoma cells

  • Biochim Biophys Acta Mol Cell Res. 2026 Feb;1873(2):120094. doi: 10.1016/j.bbamcr.2025.120094.
Ruirui Cao 1,  Yue Wu 1,  Yawei Li 1,  Mengting Shi 1,  Tiantian Zhang 1,  Weijie Sun 1,  Yang Liu 1,  Rui Wang 2
Affiliations

Affiliations

  • 1 Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, Anhui, PR China.
  • 2 Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, Anhui, PR China; Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu, 233004, Anhui, PR China. Electronic address: [email protected].
PMID: 41354180 DOI: 10.1016/j.bbamcr.2025.120094
Abstract

Hepatocellular carcinoma (HCC) is fatal and does not respond well to classical chemotherapies. This paper investigates the molecular mechanism of RIOK1 on lenvatinib resistance in HCC cells. Differentially expressed genes were identified before and after lenvatinib treatment using transcriptome Sequencing. Lenvatinib resistance in HCC cells was detected. The interaction between RIOK1 and YBX1 was assessed. YBX1, JAK2, and STAT3 phosphorylation levels were detected. The effect of YBX1 and JAK2/STAT3 pathway activator on lenvatinib resistance was analyzed. Tumor volume and weight, and Apoptosis were analyzed in lenvatinib-treated nude mice. RIOK1, YBX1, and JAK2/STAT3 were reduced in HCC cells after lenvatinib treatment. RIOK1 knockdown prevented HCC cell growth and reduced lenvatinib resistance. The interaction between RIOK1 and YBX1 induced Ser 165 phosphorylation, thereby promoting nuclear localization of YBX1. YBX1, JAK2, and STAT3 phosphorylation levels were elevated upon RIOK1 overexpression. YBX1 overexpression and JAK2/STAT3 pathway activator mitigated the Anticancer effect of RIOK1 knockdown and increased lenvatinib resistance. Tumor volume, Apoptosis, KI67, YBX1, and JAK2/STAT3 phosphorylation levels were reduced in tumor tissue after RIOK1 knockdown and increased after further YBX1 overexpression. Overall, RIOK1 activates the JAK2/STAT3 pathway by promoting YBX1 phosphorylation, leading to HCC progression and lenvatinib resistance.

Keywords

Hepatocellular carcinoma; JAK2/STAT3; Lenvatinib resistance; RIOK1; YBX1.

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