Donor graft METTL3 gene transfer ameliorates rat liver transplantation ischemia-reperfusion injury by enhancing HO-1 expression in an m6A-dependent manner
作者全名："Xiang, Song; Wang, Yihua; Lei, Dengliang; Luo, Yunhai; Peng, Dadi; Zong, Kezhen; Liu, Yanyao; Huang, Zuotian; Mo, Shaojiang; Pu, Xingyu; Zheng, Jinli; Wu, Zhongjun"
作者地址："[Xiang, Song; Wang, Yihua; Lei, Dengliang; Luo, Yunhai; Peng, Dadi; Zong, Kezhen; Liu, Yanyao; Wu, Zhongjun] Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Chongqing, Peoples R China; [Huang, Zuotian; Mo, Shaojiang] Chongqing Univ, Canc Hosp, Chongqing, Peoples R China; [Pu, Xingyu; Zheng, Jinli] Sichuan Univ, Liver Transplantat Ctr, Dept Liver Surg, West China Hosp, Chengdu, Sichuan, Peoples R China; [Wu, Zhongjun] Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China"
通信作者："Wu, ZJ (通讯作者)，Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China."
关键词：Liver transplantation; Ischemia-reperfusion injury; METTL3; N 6-methyladenosine; HO-1
摘要："Ischemia-reperfusion injury (IRI) is one of the most common complications in liver transplantation. METTL3 regulates inflammation and cellular stress response by modulating RNA m6A modification level. Here, the study aimed to investigate the role and mechanism of METTL3 in IRI after rat orthotopic liver transplantation. The total RNA m6A modification and METTL3 expression level was consistently down-regulated after 6 h or 24 h reperfusion in OLT, which is negatively associated with the hepatic cell apoptosis. Functionally, METTL3 pretreatment in donor significantly inhibited liver grafts apoptosis, improved liver function and depressed the proinflammatory cytokine/chemokine expression. Mechanistically, METTL3 inhibited apoptosis of grafts via upregulating HO-1. Moreover, m6A dot blot and MeRIP-qPCR assay revealed that METTL3 promoted HO-1 expression in an m6A-dependent manner. In vitro, METTL3 alleviated hepatocytes apoptosis by upregulating HO-1 under hypoxia/reoxygenation condition. Taken together, these findings demonstrate that METTL3 ameliorates rat OLTstressed IRI by inducing HO-1 in an m6A-dependent manner, highlighting a potential target for IRI in liver transplantation."
基金机构："National Natural Science Foundation of China [82170666, 81873592]"
基金资助正文：Funding This work was supported by the grants from the National Natural Science Foundation of China (No. 82170666 and No. 81873592) .