Metronomic capecitabine inhibits liver transplant rejection in rats by triggering recipients’T cell ferroptosis  

作　　者：Hao Wang Zheng-Lu Wang Sai Zhang De-Jun Kong Rui-Ning Yang Lei Cao Jian-Xi Wang Sei Yoshida Zhuo-Lun Song Tao Liu Shun-Li Fan Jia-Shu Ren Jiang-Hong Li Zhong-Yang Shen Hong Zheng 

机构地区：[1]The First Central Clinical School,Tianjin Medical University,Tianjin 300190,China [2]Department of Organ Transplant,Tianjin First Central Hospital,School of Medicine,Nankai University,Tianjin 300190,China [3]Key Laboratory of Transplant Medicine,Chinese Academy of Medical Sciences,Tianjin 300190,China [4]School of Medicine,Nankai University,Tianjin 300190,China [5]Research Institute of Transplant Medicine,Nankai University,Tianjin 300071,China [6]Tianjin Key Laboratory for Organ Transplantation,Tianjin First Central Hospital,School of Medicine,Nankai University,Tianjin 300071,China [7]National Health Commission’s Key Laboratory for Critical Care Medicine,Tianjin First Central Hospital,Tianjin 300071,China

出　　处：《World Journal of Gastroenterology》2023年第20期3084-3102,共19页世界胃肠病学杂志（英文版）

基　　金：Supported by National Key Research and Development Program of China,No.2020YFA0710802;The Youth Science Fund of the Nature Science Foundation of Tianjin,No.20JCQNJC01370;The Key Projects of Tianjin Science and Technology Project,No.21JCZDJC00160;The Science Foundation of Tianjin Health Commission,No.ZC20065 and No.ZC20089.

摘　　要：BACKGROUND Capecitabine(CAP)is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation(LT)in clinical studies.Our previous study showed that metronomic CAP can cause the programmed death of T cells by inducing oxidative stress in healthy mice.Ferroptosis,a newly defined non-apoptotic cell death that occurs in response to iron overload and lethal levels of lipid peroxidation,is an important mechanism by which CAP induces cell death.Therefore,ferroptosis may also play an important role in CAP-induced T cell death and play an immunosuppressive role in acute rejection after transplantation.AIM To investigate the functions and underlying mechanisms of antirejection effects of metronomic CAP.METHODS A rat LT model of acute rejection was established,and the effect of metronomic CAP on splenic hematopoietic function and acute graft rejection was evaluated 7 d after LT.In vitro,primary CD3+T cells were sorted from rat spleens and human peripheral blood,and co-cultured with or without 5-fluorouracil(5-FU)(active agent of CAP).The levels of ferroptosis-related proteins,ferrous ion concentration,and oxidative stress-related indicators were observed.The changes in mitochondrial structure were observed using electron microscopy.RESULTS With no significant myelotoxicity,metronomic CAP alleviated graft injury(Banff score 9 vs 7.333,P<0.001),prolonged the survival time of the recipient rats(11.5 d vs 16 d,P<0.01),and reduced the infiltration rate of CD3+T cells in peripheral blood(6.859 vs 3.735,P<0.001),liver graft(7.459 vs 3.432,P<0.001),and spleen(26.92 vs 12.9,P<0.001),thereby inhibiting acute rejection after LT.In vitro,5-FU,an end product of CAP metabolism,induced the degradation of the ferritin heavy chain by upregulating nuclear receptor coactivator 4,which caused the accumulation of ferrous ions.It also inhibited nuclear erythroid 2 p45-related factor 2,heme oxygenase-1,and glutathione peroxidase 4,eventually leading to oxidative damage and ferroptosis of T cells.CONCLUSION

关 键 词：CAPECITABINE Ferroptosis T Lymphocytes Immunosuppressive agents Graft rejection Liver transplantation 

分 类 号：R657.3[医药卫生—外科学]