Ferroptosis and Acetaminophen Hepatotoxicity: Are We Going Down Another Rabbit Hole?

Abstract

Acetaminophen (APAP) hepatotoxicity is the most frequent cause of acute liver failure in the US. The mechanisms of APAP-induced liver injury have been under extensive investigations for decades, and many key events of this necrotic cell death are known today. Initially, two opposing hypotheses for cell death were proposed: reactive metabolite and protein adduct formation versus reactive oxygen and lipid peroxidation (LPO). In the end, both mechanisms were reconciled, and it is now generally accepted that the toxicity starts with formation of reactive metabolites that, after glutathione depletion, bind to cellular proteins, especially on mitochondria. This results in a mitochondrial oxidant stress, which requires amplification through a mitogen-activated protein kinase cascade, leading ultimately to enough reactive oxygen and peroxynitrite formation to trigger the mitochondrial membrane permeability transition and cell death. However, the earlier rejected LPO hypothesis seems to make a comeback recently under a different name: ferroptosis. Therefore, the objective of this review was to critically evaluate the available information about intracellular signaling mechanisms of APAP-induced cell death and those of ferroptosis. Under pathophysiologically relevant conditions, there is no evidence for quantitatively enough LPO to cause cell death, and thus APAP hepatotoxicity is not caused by ferroptosis. However, the role of mitochondria-localized minor LPO remains to be further investigated.