Excessive
acetaminophen (
APAP) use is one of the most common causes of
acute liver failure. Various types of cell death in the damaged liver are linked to
APAP-induced hepatotoxicity, and, of these, necrotic cell death of hepatocytes has been shown to be involved in disease pathogenesis. Until recently,
necrosis was commonly considered to be a random and unregulated form of cell death; however, recent studies have identified a previously unknown form of programmed
necrosis called receptor-interacting
protein kinase (RIPK)-dependent
necrosis (or necroptosis), which is controlled by the
kinases RIPK1 and RIPK3. Although RIPK-dependent
necrosis has been implicated in a variety of disease states, including
atherosclerosis, myocardial organ damage,
stroke,
ischemia-reperfusion injury,
pancreatitis, and
inflammatory bowel disease. However its involvement in
APAP-induced hepatocyte
necrosis remains elusive. Here, we showed that RIPK1 phosphorylation, which is a hallmark of RIPK-dependent
necrosis, was induced by
APAP, and the expression pattern of RIPK1 and RIPK3 in the liver overlapped with that of
CYP2E1, whose activity around the central vein area has been demonstrated to be critical for the development of
APAP-induced hepatic injury. Moreover, a RIPK1 inhibitor ameliorated
APAP-induced hepatotoxicity in an animal model, which was underscored by significant suppression of the release of hepatic
enzymes and
cytokine expression levels. RIPK1 inhibition decreased
reactive oxygen species levels produced in
APAP-injured hepatocytes, whereas
CYP2E1 expression and the depletion rate of total
glutathione were unaffected. Of note, RIPK1 inhibition also conferred resistance to oxidative stress in hepatocytes. These data collectively demonstrated a RIPK-dependent necrotic mechanism operates in the
APAP-injured liver and inhibition of this pathway may be beneficial for
APAP-induced
fulminant hepatic failure.