肝移植是治疗肝癌最有效的方法之一。在肝移植后抑制免疫排斥反应和预防肿瘤复发之间的平衡是决定肝癌患者移植后长期预后的关键因素。在我们之前的研究中，我们发现卡培他滨（CAP），一种有效治疗肝癌的药物，能通过诱导T细胞铁死亡发挥移植后免疫抑制作用。最近的研究表明，铁死亡与自噬密切相关。在本研究中，我们确认自噬诱导剂雷帕霉素（RAPA）与间隔给药的卡培他滨（mCAP）联合使用，抑制谷胱甘肽过氧化物酶4（GPX4），促进CD4 + T细胞的铁死亡作用，发挥移植后免疫抑制效果。与单独使用RAPA或mCAP相比，RAPA和mCAP的联合可有效减少移植后急性排斥反应中大鼠的肝损伤。受体大鼠的外周血、脾脏和移植肝中的CD4 + T细胞计数显著降低，组合组中CD4 + T细胞的氧化应激水平和铁离子浓度显著增加。体外实验中，这些药物的联合显著促进了自噬，降低了CD4 + T细胞中GPX4蛋白的表达，并诱导了铁死亡。总之，自噬诱导剂RAPA改善了mCAP引起的CD4 + T细胞铁死亡。我们的研究结果支持了铁死亡作为自噬依赖性细胞死亡的概念，并提出了联合铁死亡诱导剂和自噬诱导剂作为改善肝移植后免疫抑制方案的新研究方向。版权所有© 2023 The Authors. Elsevier B.V.保留所有权利。

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.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.