Donor graft METTL3 gene transfer ameliorates rat liver transplantation ischemia-reperfusion injury by enhancing HO-1 expression in an m6A-dependent manner

Ischemia-reperfusion injury (IRI) is one of the most common complications in liver transplantation. METTL3 regulates inflammation and various cellular stress responses via modulating RNA m6A modification level. Here, the study aimed to investigate the role and mechanism of METTL3 in IRI after rat orthotopic liver transplantation. Firstly, m6A dot blot assay showed that total RNA m6A modification level in grafts was down-regulated, which echoed with the downregulation of METTL3. Furthermore, METTL3 pretreatment in donor significantly reduced liver grafts necrosis formation, Apoptosis, improved liver function and depressed the proinflammatory cytokine/chemokine expression. Mechanistically, western blot and immunohistochemical showed that METTL3 inhibited Apoptosis via upregulating HO-1. Moreover, MeRIP-qPCR assay revealed that METTL3 promoted HO-1 expression in an m6A-dependent manner. Additionally, METTL3 alleviated primary hepatocytes Apoptosis by upregulating HO-1 under hypoxia/reoxygenation condition. Taken together, these results demonstrated that METTL3 exerted a cytoprotective role against IRI via inducing HO-1 in an m6A-dependent manner.

HO-1; Ischemia-reperfusion injury; Liver transplantation; METTL3; N(6)-methyladenosine.