KYNA Ameliorates Hepatic Ischemia-Reperfusion Injury by Activating the Hippo Signalling Pathway via FTO-Dependent m6A Demethylation of LATS1.

Abstract

Hepatic ischemia-reperfusion injury (HIRI) substantially influences the prognosis of liver transplant recipients. Although kynurenic acid (KYNA) has been associated with protective effects against ischemia-reperfusion injury in various organs, the precise mechanisms underlying its protective role in HIRI are not well elucidated. In this study, a 70% mouse HIRI model and an in vitro hypoxia/reoxygenation model were employed to examine the protective effects of KYNA on HIRI. In this study, we illustrate that KYNA influences the methylation status of the Hippo signalling pathway by enhancing the expression of the fat mass and obesity-associated gene (FTO). Within this pathway, large tumour suppressor kinase 1 (LATS1) is identified as a direct target of FTO. Moreover, the stability of LATS1 mRNA exhibits an inverse correlation with FTO levels and is modulated through its interaction with YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2). The reduction in LATS1 expression facilitated Yes-associated protein (YAP) nuclear translocation, decreased hepatocyte apoptosis, and mitigated HIRI. Clinically, elevated levels of serum KYNA correlate with a diminished severity of liver injury post-transplantation. our work revealed that KYNA possesses significant clinical translational potential for the prevention of HIRI, and further exploration of its underlying mechanisms was conducted.