2. Academic Validation
  3. Circular RNA CDYL facilitates hepatocellular carcinoma stemness and PD-L1+ exosomes-mediated immunotherapy resistance via stabilizing hornerin protein by blocking synoviolin 1-mediated ubiquitination

Circular RNA CDYL facilitates hepatocellular carcinoma stemness and PD-L1+ exosomes-mediated immunotherapy resistance via stabilizing hornerin protein by blocking synoviolin 1-mediated ubiquitination

  • Int J Biol Macromol. 2025 May;310(Pt 4):143246. doi: 10.1016/j.ijbiomac.2025.143246.
Jingbo Fu 1,  Fuyan Liu 2,  Shilei Bai 3,  Xue Jiang 4,  Hao Song 5,  Man Zhang 5,  Ru Zhao 5,  Tao Ouyang 5,  Miao Yu 4,  Haihua Qian 4,  Shuo Xu 5,  Yunfei Huo 4,  Xinwei Yang 6,  Lu Chen 4,  Dan Cao 7,  Tao Guo 8,  Yanping Wei 9,  Liang Li 10,  Hongyang Wang 1
Affiliations

Affiliations

  • 1 Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China.
  • 2 Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; National Center for Liver Cancer, Shanghai, China.
  • 3 Department of Hepatic Surgery II, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
  • 4 National Center for Liver Cancer, Shanghai, China.
  • 5 International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China.
  • 6 Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
  • 7 International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.
  • 8 Department of integrated traditional Chinese and Western Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
  • 9 Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China. Electronic address: weiyanpv@sina.com.
  • 10 Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China. Electronic address: liliangyuanquan@163.com.
PMID: 40250664 DOI: 10.1016/j.ijbiomac.2025.143246
Abstract

Despite the revolutionary progress in Cancer Immunotherapy, only a minority of hepatocellular carcinoma (HCC) patients respond to immune checkpoint inhibitors (ICIs). In this study, we found that the oncogenic circular RNA Circ-CDYL in HCC influences the efficacy of immunotherapy and the stemness characteristics of HCC cells by interacting with the hornerin (HRNR) protein. The degraded anti-PD-L1 immunotherapy responses induced by Circ-CDYL and HRNR were confirmed by peripheral blood mononuclear cells (PBMCs) killing assays in HCC cells, patient-derived organoids, and humanized immune system mouse models. Furthermore, Circ-CDYL interference reversed the cytotoxicity and proliferation of CD8+ T cells, resulting in ameliorated immune evasion in tumor spheroids upon anti-PD-L1 treatment. Mechanistically, Circ-CDYL upregulated HRNR expression by stabilizing the HRNR protein through the prevention of its degradation by the E3 ubiquitin Ligase synoviolin 1 (SYVN1), which in sequence promoted the phosphorylation of the mTORC1 and p70S6K substrate. The abnormally activated mTORC1-p70S6K signaling increases the stemness of HCC cells and upregulates PD-L1 expression, which may attenuate anti-PD-L1 therapy efficacy via PD-L1+ exosomes. Our study revealed the mechanism by which Circ-CDYL and HRNR regulate the sensitivity of HCC to anti-PD-L1 therapy, and the findings have potential implications for patient stratification and clinical decision-making in HCC immunotherapy.

Keywords

Circular RNA; Exosomes; Hepatocellular carcinoma; Immunotherapy resistance; Stemness.

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