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Although ERK pathway is shown to be involved in T\u2010cell activation, little is known about its role in the development of allograft rejection. Here, it is reported that ERK signaling pathway is activated in allograft\u2010infiltrating T cells. On the basis of surface plasmon resonance technology, lycorine is identified as an ERK\u2010specific inhibitor. ERK inhibition by lycorine significantly prolongs allograft survival in a stringent mouse cardiac allotransplant model. As compared to untreated mice, lycorine\u2010treated mice show a decrease in the number and activation of allograft\u2010infiltrated T cells. It is further confirmed that lycorine\u2010treated mouse and human T cells are less responsive to stimulation in vitro, as indicated by their low proliferative rates and decreased cytokine production. Mechanistic studies reveal that T cells treated with lycorine exhibit mitochondrial dysfunction, resulting in metabolic reprogramming upon stimulation. Transcriptome analysis of lycorine\u2010treated T cells reveals an enrichment in a series of downregulated terms related to immune response, the mitogen\u2010activated protein kinase cascade, and metabolic processes. These findings offer new insights into the development of immunosuppressive agents by targeting the ERK pathway involved in T\u2010cell activation and allograft rejection.<\/jats:p>","DOI":"10.1002\/advs.202206768","type":"journal-article","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T06:15:32Z","timestamp":1680588932000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T\u2010Cell Metabolism"],"prefix":"10.1002","volume":"10","author":[{"given":"Xiaosheng","family":"Tan","sequence":"first","affiliation":[{"name":"Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology   Wuhan Hubei Province 430030 P. R. China"},{"name":"Key Laboratory of Organ Transplantation Ministry of Education Chinese Academy of Medical Sciences  Wuhan Hubei Province 430030 P. R. 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