Dissecting the molecular pathophysiology of drug-induced liver injury

Figure 3 Schematic overview of three different modes of cell death: apoptosis, necrosis and necroptosis. When FasL or Tumor necrosis factor-alpha (TNF-α) bind to their death receptors (DRs), death domains of DRs are oligomerized and form death-inducing signalling complex (DISC), which recruits caspase-8. Active caspase 8 cleaves Bid into cleaved Bid (tBid), which translocates to mitochondria and cooperates with Bax. Meanwhile, JNKs are activated by Mitogen-activated protein kinases (MAPKs) and pJNK also translocates to the mitochondria via binding to the Sab protein. ROS accumulation and ATP depletion in the mitochondria aggravate mitochondrial damage and induce membrane permeability transition (MPT), resulting in release of cytochrome C, in turn promoting the activation of caspase-9 and caspase-3. Activated caspase-3 then leads to hepatocyte apoptosis. The extrinsic and intrinsic pathways of hepatocyte apoptosis are linked, because hepatocytes require mitochondrial amplification activating caspase-3 for cell death execution. The mitochondrial injury and MPT are also key factors in cascade of events leading to necrosis. Necroptosis shares the upstream pathway with apoptosis. When cellular inhibitors of apoptosis (cIAPs) are depleted, Receptor interacting protein kinase (RIPK)1 and RIPK3 interact with each other via membrane permeability transition (RHIM) domains to form the necrosome, and further recruit and phosphorylate MLKL to initiate necroptosis.