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

被引：5

作者：

Wang, Hao ^{[1
]}

Wang, Zheng-Lu ^{[2
,3
]}

Zhang, Sai ^{[4
]}

Kong, De-Jun ^{[4
]}

Yang, Rui-Ning ^{[1
]}

Cao, Lei ^{[5
,6
]}

Wang, Jian-Xi ^{[5
,6
]}

Yoshida, Sei ^{[5
]}

Song, Zhuo-Lun ^{[2
]}

Liu, Tao ^{[7
]}

Fan, Shun-Li ^{[2
]}

Ren, Jia-Shu ^{[1
]}

Li, Jiang-Hong ^{[1
]}

Shen, Zhong-Yang ^{[2
,3
,5
,6
,7
]}

Zheng, Hong ^{[2
,3
,5
,6
,7
,8
]}

机构：

[1] Tianjin Med Univ, Cent Clin Sch 1, Tianjin 300190, Peoples R China

[2] Nankai Univ, Tianjin Cent Hosp 1, Sch Med, Dept Organ Transplant, Tianjin 300190, Peoples R China

[3] Chinese Acad Med Sci, Key Lab Transplant Med, Tianjin 300190, Peoples R China

[4] Nankai Univ, Sch Med, Tianjin 300190, Peoples R China

[5] Nankai Univ, Res Inst Transplant Med, Tianjin 300071, Peoples R China

[6] Nankai Univ, Tianjin Cent Hosp 1, Sch Med, Tianjin Key Lab Organ Transplantat, Tianjin 300071, Peoples R China

[7] Tianjin First Cent Hosp, Natl Hlth Commiss Key Lab Crit Care Med, Tianjin 300071, Peoples R China

[8] Nankai Univ, Tianjin Cent Hosp 1, Sch Med, Dept Organ Transplant, 24 Fukang Rd, Tianjin 300190, Peoples R China

来源：

WORLD JOURNAL OF GASTROENTEROLOGY | 2023年 / 29卷 / 20期

关键词：

Capecitabine; Ferroptosis; T Lymphocytes; Immunosuppressive agents; Graft rejection; Liver transplantation; HEPATOCELLULAR-CARCINOMA; LIPID-PEROXIDATION; ACTIVATION; MYELOSUPPRESSION; CHEMOTHERAPY; GLUTATHIONE; SORAFENIB; PHASE;

D O I：

10.3748/wjg.v29.i20.3084

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

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 Metronomic CAP can suppress acute allograft rejection in rats by triggering CD3(+) T cell ferroptosis, which makes it an effective immunosuppressive agent after LT. (c) The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.

引用

页码：3084 / 3102

页数：19