Fig. 6.

Schematic illustration of the model for the protective effect(s) of Nec-1 against acetaminophen (APAP)-induced hepatocyte necrosis. APAP is converted to the highly reactive metabolite NAPQI by CYP2E1 and other cytochrome P450 enzymes (CYPs) in the liver. NAPQI is inactivated by conjugation to GSH and detoxified. However, excess NAPQI leads to GSH depletion and unconjugated NAPQI binds to cellular proteins, causing further formation of ROS. Resultant oxidative injuries, including mitochondria dysfunction, result in massive hepatic necrosis. Although the mechanism of RIPK1 activation remains unclear, Nec-1 inhibits necrosome formation and intracellular ROS production, which eventually prevent RIPK-dependent necrosis. ROS and reactive nitrogen species (RNS) produced by living cells and/or leaked from dead cells (extracellular ROS/RNS) also provoke hepatocyte cell death. By unknown mechanisms, Nec-1 also inhibits this cell death pathway.