Nifuroxazide suppresses PD-L1 expression and enhances the efficacy of radiotherapy in hepatocellular carcinoma

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Abstract
Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.
Funding Information
  • Doctor Launch Fund of Xinxiang Medical University (505017)
  • Doctor Launch Fund of Xinxiang Medical University (505016)
  • Doctor Launch Found of Xinxiang Medical University (502006)
  • Key Projects of Scientific Research for Higher Education of Henan Province (21A310012)
  • Young Backbone Teacher Training Projects of Universities in Henan province (2020GGJS149)
  • Science and Technology Research Project of Henan Province (222102310016)
  • Major Science and Technology Project of Xinxiang City (ZD2020005)
  • Science and technology Project of Xinxiang (GG2019043)
  • Medical Education Research Project of Henan Province (Wjlx2020305)
  • Teaching and Scientific Research Program of Basic Medical College, Xinxiang Medical University (JCYXYJX202006)
  • Graduate Student Innovation Support Plan (YJSCX202149Y)
  • Innovation and Entrepreneurship Training Program for College Student (202210472005)
  • Key Research and Development Projects in Henan Province (231111311300)

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