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

Abstract

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.

Quercetin improves diabetic kidney disease by inhibiting ferroptosis and regulating the Nrf2 in streptozotocin-induced diabetic rats

“…Nrf2, a critical transcription factor, has been widely recognized not only as a pivotal gene in antioxidant defense mechanisms but also as an essential mediator in the process of ferroptosis [ 30 ]. The upregulation of Nrf2 can provide protection against cell damage induced by ferroptosis [ 40 ]. Recent studies have shown that the activation of Nrf2 plays a significant role in influencing the progression of endothelial injury and acute kidney injury by regulating oxidative stress and lipid peroxidation [ 41 , 42 ].…”

Effect of sulfasalazine on ferroptosis during intestinal injury in rats after liver transplantation

“…Ferrostain-1 is an effective and selective ferroptosis inhibitor. It prevents membrane lipid damage through a reduction mechanism and eliminates lipid ROS produced by the body by inhibiting the enzyme-mediated process catalyzed by iron-dependent lipoxygenase, thereby inhibiting cell death [23][24][25][26][27][28] . SAS is an important drug for the treatment of ulcerative colitis and is also one of the most commonly used anti-inflammatory drugs in clinical practice.…”