Matrine is an alkaloid extracted from Sophora flavescens Ait and has been found to exhibit many biological activities,such as anti-inflammation,antitumor,anti-fibrosis,and immunosuppression.In our previous studies,the matrine derivative,MASM was synthesized and exhibited potent inhibitory activity against liver fibrosis.In this study,we mainly investigated its protection to rats against lethal total-body irradiation(TBI).Pre-administration or administration of MASM reduced the radiation sickness characteristics,while increasing the 30 day-survival of the irradiated rats.Ultrastructural observation illustrated that pretreatment of rats with MASM significantly attenuated the TBI-induced morphological changes in the different organs of irradiated rats.Gene expression profiles revealed that pretreatment with MASM had a dramatic effect on gene expression changes caused by TBI.Pretreatment with MASM prevented differential expression of 53%(765 genes)of 1445 differentially expressed genes induced by TBI.Pathway enrichment analysis indicated that these genes were mainly involved in a total of 21 pathways,such as metabolic pathways,pathways in cancer,and mitogen-activated protein kinase(MAPK)pathways.Our data indicated that pretreatment of rats with MASM modulated these pathways induced by TBI,suggesting that the pretreatment with MASM might provide the protective effects on lethal TBI mainly or partially through the modulation of these pathways,such as multiple MAPK pathways.Therefore,MASM has the potential to be used as an effective therapeutic or radioprotective agent to minimize irradiation damages and in combination with radiotherapy to improve the efficacy of cancer therapy.