2. Academic Validation
  3. Metronomic capecitabine with rapamycin exerts an immunosuppressive effect by inducing ferroptosis of CD4+ T cells after liver transplantation in rat

Metronomic capecitabine with rapamycin exerts an immunosuppressive effect by inducing ferroptosis of CD4+ T cells after liver transplantation in rat

  • Int Immunopharmacol. 2023 Aug 23;124(Pt A):110810. doi: 10.1016/j.intimp.2023.110810.
Hao Wang 1,  Ruining Yang 1,  Zhenglu Wang 2,  Lei Cao 3,  Dejun Kong 4,  Qian Sun 1,  Sei Yoshida 5,  Jiashu Ren 1,  Tao Chen 4,  Jinliang Duan 4,  Jianing Lu 1,  Zhongyang Shen 6,  Hong Zheng 7
Affiliations

Affiliations

  • 1 The First Central Clinical School, Tianjin Medical University, Tianjin, China.
  • 2 Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
  • 3 Research Institute of Transplant Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.
  • 4 School of Medicine, Nankai University, Tianjin, China.
  • 5 Research Institute of Transplant Medicine, Nankai University, Tianjin, China.
  • 6 Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Research Institute of Transplant Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin, China.
  • 7 Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Research Institute of Transplant Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China; National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin, China. Electronic address: zhenghongyx@139.com.
PMID: 37625370 DOI: 10.1016/j.intimp.2023.110810
Abstract

Liver transplantation is one of the most effective treatments for hepatocellular carcinoma (HCC). The balance between inhibiting immune rejection and preventing tumor recurrence after liver transplantation is the key to determining the long-term prognosis of patients with HCC after liver transplantation. In our previous study, we found that capecitabine (CAP), an effective drug for the treatment of HCC, could exert an immunosuppressive effect after liver transplantation by inducing T cell Ferroptosis. Recent studies have shown that Ferroptosis is highly associated with Autophagy. In this study, we confirmed that the Autophagy inducer rapamycin (RAPA) combined with metronomic capecitabine (mCAP) inhibits Glutathione Peroxidase 4 (GPX4) and promotes Ferroptosis in CD4+ T cells to exert immunosuppressive effects after rat liver transplantation. Compared with RAPA or mCAP alone, the combination of RAPA and mCAP could adequately reduce liver injury in rats with acute rejection after transplantation. The CD4+ T cell counts in peripheral blood, spleen, and transplanted liver of recipient rats significantly decreased, and the oxidative stress level and ferrous ion concentration of CD4+ T cells significantly increased in the combination group. In vitro, the combination of drugs significantly promoted Autophagy, decreased GPX4 protein expression, and induced Ferroptosis in CD4+ T cells. In conclusion, the Autophagy inducer RAPA improved the mCAP-induced Ferroptosis in CD4+ T cells. Our results support the concept of Ferroptosis as an autophagy-dependent cell death and suggest that the combination of Ferroptosis inducers and Autophagy inducers is a new research direction for improving immunosuppressive regimens after liver transplantation.

Keywords

Acute rejection; Autophagy; Capecitabine; Ferroptosis; Immunosuppressive agents; Rapamycin.

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