FTO deficiency in older livers exacerbates ferroptosis during ischaemia/reperfusion injury by upregulating ACSL4 and TFRC

ABSTRACT: Older livers are more prone to hepatic ischaemia/reperfusion injury (HIRI), which severely limits their utilization in liver transplantation (LT); however, the potential mechanism remains unclear. Here, we demonstrated older livers exhibit a higher degree of ferroptosis during HIRI. Inhibiting ferroptosis significantly attenuated older HIRI. Mass spectrometry revealed fat mass and obesity-associated gene (FTO) was downregulated in older livers, especially during HIRI. Overexpressing FTO ameliorated older HIRI by inhibiting ferroptosis. Mechanistically, ACSL4 and TFRC, two key positive contributors of ferroptosis, were targets of FTO. The mitigating effect of FTO on older HIRI required the inhibition of Acsl4 and Tfrc mRNA stability in a m6A-dependent manner. Furthermore, we demonstrated nicotinamide mononucleotide (NMN) could upregulate FTO demethylase activity to suppress ferroptosis and attenuate older HIRI. Collectively, these findings revealed an FTO-ACSL4/TFRC regulatory pathway that contributes to the pathogenesis of older HIRI, providing insight into the clinical translation of strategies related to the demethylase activity of FTO in order to improve graft function after older donor LT.

ORGANISM(S): Mus Musculus

SUBMITTER: Yang Yang  

PROVIDER: PXD051387 | iProX | Fri Apr 12 00:00:00 BST 2024

REPOSITORIES: iProX