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©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
Metronomic capecitabine inhibits liver transplant rejection in rats by triggering recipients’ T cell ferroptosis
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
Hao Wang, Rui-Ning Yang, Jia-Shu Ren, Jiang-Hong Li, The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
Zheng-Lu Wang, Zhuo-Lun Song, Shun-Li Fan, Zhong-Yang Shen, Hong Zheng, Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
Zheng-Lu Wang, Zhong-Yang Shen, Hong Zheng, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300190, China
Sai Zhang, De-Jun Kong, School of Medicine, Nankai University, Tianjin 300190, China
Lei Cao, Jian-Xi Wang, Sei Yoshida, Zhong-Yang Shen, Hong Zheng, Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
Lei Cao, Jian-Xi Wang, Zhong-Yang Shen, Hong Zheng, Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
Tao Liu, Zhong-Yang Shen, Hong Zheng, National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300071, China
Author contributions: Wang H conceived the study, performed the experiments, analyzed the data, generated the figures, and wrote the manuscript; Wang ZL, Zhang S, and Kong DJ provided technical help and assisted with the experiments; Zhang S, Kong DJ, Yang RN, Cao L, and Wang JX helped with the data analyses; Wang ZL, Yoshida S, Zhang S, Liu T, Shen ZY, and Zheng H performed critical reading of the manuscript; Fan SL, Ren JS, Li JH, and Zheng H assisted with the editing and writing of the manuscript; Zheng H supervised the study and edited the manuscript.
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; and The Science Foundation of Tianjin Health Commission, No. ZC20065 and No. ZC20089.
Institutional review board statement: The studies involving human participants were conducted in accordance with the Declaration of Helsinki (1964) and were reviewed and approved by the Tianjin First Hospital clinical research ethics committee, No. 2022N150KY. The participants provided written informed consent to participate in this study.
Institutional animal care and use committee statement: The animal study was reviewed and approved by the ethics committee of the Institute of Radiation Medicine of the Chinese Academy of Medical Sciences, No. IRM-DWLL-2021184.
Informed consent statement: All study participants or their legal guardian provided informed written consent about personal and medical data collection prior to study enrolment.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Hong Zheng, PhD, Professor, Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, No. 24 Fukang Road, Nankai District, Tianjin 300190, China. zhenghongyx@139.com
Received: January 21, 2023
Peer-review started: January 21, 2023
First decision: February 7, 2023
Revised: February 19, 2023
Accepted: April 28, 2023
Article in press: April 28, 2023
Published online: May 28, 2023
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 trans-plantation.
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 mito-chondrial 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
Metronomic CAP can suppress acute allograft rejection in rats by triggering CD3+ T cell ferroptosis, which makes it an effective immunosuppressive agent after LT.
Core Tip: Our studies proved that metronomic capecitabine (CAP) alleviated the acute rejection after transplantation in rats without the common side effect of myelosuppression. T cell ferroptosis is the underlying mechanism behind the antirejection effect of CAP, which can induce cell ferrous ions overload and suppress the nuclear erythroid 2 p45-related factor 2, heme oxygenase-1/glutathione peroxidase 4 antioxidant systems, thereby directly increasing the levels of intracellular reactive oxygen species, and leading to severe oxidative damage in T cells. These results revealed a new mechanism of CAP-induced T cell programmed death and suggested the possibility of using CAP as an immunosuppressant after transplantation.
