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.