# miRNA biomarkers to predict risk of primary non-function of fatty allografts and drug induced acute liver failures

## TL;DR

This study identifies miRNA biomarkers that can predict the risk of primary non-function of fatty liver transplants and drug-induced liver failure.

## Contribution

The study validates 11 miRNA biomarkers for PNF and shows their relevance in both PNF and ALF.

## Key findings

- miRNA-27b-3p, miRNA-122-3p, and others correlate with hepatic steatosis grades.
- Nine PNF-associated miRNAs are also regulated in drug-induced ALF.
- Biomarker candidates show selectivity and specificity in blood samples post-OLT.

## Abstract

Primary non-function (PNF) of an allograft defines an irreversible graft failure and although rare, constitutes a life-threatening condition that requires high-urgency re-transplantation. Equally, drug induced acute liver failures (ALF) are seldom but the rapid loss of hepatic function may require orthotropic liver transplantation (OLT). Recently, we reported the development of a rodent PNF-disease model of fatty allografts and showed that a dysfunctional Cori and Krebs cycle and inhibition of lactate transporters constitute a mechanism of PNF. Based on findings from the rat PNF-disease model, we selected 15 miRNA-biomarker candidates for clinical validation and performed RT-qPCRs in well-documented PNF cases following OLT of fatty allografts. To assess specificity and selectivity, we compared their regulation in pre- and intraoperative liver biopsies and pre- and post-operative blood samples of patients undergoing elective hepatobiliary surgery. Additionally, we assessed their regulation in drug induced ALF. We confirmed clinical relevance for 11 PNF-associated miRNAs and found expression of miRNA-27b-3p, miRNA-122-3p, miRNA-125a-5p, miRNA-125b-5p and miRNA-192-5p to correlate with the hepatic steatosis grades. Furthermore, we demonstrate selectivity and specificity for the biomarker candidates with opposite regulation of let-7b-5p, miRNA-122-5p, miRNA-125b-5p and miRNA-194-5p in blood samples of patients following successful OLTs and/or liver resection. Moreover, by considering findings from 21 independent ALF-studies, we observed nine PNF-associated miRNAs regulated in common. We report miRNAs highly regulated in PNF and ALF, and their common regulation in different diseases broadens the perspective as biomarker candidates. Our study warrants independent confirmation in randomized clinical trials.

Created in BioRender. Schönberg, J. (2024) BioRender.com/e21p058

The online version contains supplementary material available at 10.1007/s11010-024-05129-3.