vtRNA1-1 drives regorafenib resistance by sustaining cancer stemness via impaired autophagy and altered svRNA biogenesis

  • Int J Biol Macromol. 2025 Sep 7;328(Pt 1):147514. doi: 10.1016/j.ijbiomac.2025.147514.
Yafei Wu  1 ,  Wenjing Diao  1 ,  Xue Zhang  2 ,  Dahong Chen  1 ,  Huihua Yang  1 ,  Lin Zhong  3 ,  Chuanxing Wu  4 ,  Qin Li  5
Affiliations
  • 1. Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Shanghai, 200080, PR China.
  • 2. Shanghai Eye Diseases Prevention &Treatment Center/Shanghai Eye Hospital, School of Medicine, Tongji University, PR China.
  • 3. Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Shanghai, 200080, PR China.
  • 4. Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Shanghai, 200080, PR China. Electronic address: [email protected].
  • 5. Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Shanghai, 200080, PR China; Shanghai Eye Diseases Prevention &Treatment Center/Shanghai Eye Hospital, School of Medicine, Tongji University, PR China. Electronic address: [email protected].
PMID: 40925433 DOI: 10.1016/j.ijbiomac.2025.147514
Abstract

While vault RNA1-1 (vtRNA1-1) has been implicated in tumor biology, its specific role in Cancer stemness and regorafenib resistance remains unexplored. In this study, we identify vtRNA1-1 as a critical regulator of Cancer stemness and chemoresistance in Hepatocellular carcinoma (HCC). vtRNA1-1 enhances stemness properties by modulating the nuclear accumulation of Nanog, a core transcription factor. This pro-stemness effect could be counteracted through Autophagy activation using rapamycin or nutrient starvation. Importantly, we demonstrate that regorafenib treatment induces vtRNA1-1 upregulation, and that acquired resistance correlates with impaired vtRNA1-1 processing, leading to vtRNA1-1 accumulation and reduced generation of small vault RNAs (svRNAs). Genetic silencing of vtRNA1-1 effectively restored regorafenib sensitivity in resistant cells by promoting Apoptosis and suppressing stemness markers. Our findings establish vtRNA1-1 as a novel oncogenic driver and reveal its potential as both a predictive biomarker for regorafenib response and a therapeutic target for overcoming drug resistance.

Keywords
Regorafenib resistance; Stemness; Vault RNA1-1.
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