Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway

SUMMARY
Drug-induced liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the
Western world. Acetaminophen (APAP) overdose is a main contributor of DILI, leading to hepatocyte cell
death through necrosis. Here, we identified that neddylation, an essential post-translational modification
involved in the mitochondria function, was upregulated in liver biopsies from patients with APAP-induced
liver injury (AILI) and in mice treated with an APAP overdose. MLN4924, an inhibitor of the neuronal precursor
cell-expressed developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE-1), ameliorated
necrosis and boosted liver regeneration in AILI. To understand how neddylation interferes in AILI, wholebody
biotinylated NEDD8 (bioNEDD8) and ubiquitin (bioUB) transgenic mice were investigated under APAP
overdose with and without MLN4924. The cytidine diphosphate diacylglycerol (CDP-DAG) synthase
TAM41, responsible for producing cardiolipin essential for mitochondrial activity, was found modulated under
AILI and restored its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is
essential for developing promising targeted inhibitors for DILI treatment.