Figure 4.

Molecular mechanisms pertaining to four types of nonapoptotic regulated cell deaths. Top left: necroptosis is triggered by receptor-interacting serine/threonine-protein kinase (RIPK)1 activation upon binding between death receptor and death ligand. RIPK1 then phosphorylates RIPK3, leading to the assembly of necrosome, where mixed lineage kinase domain-like (MLKL) is recruited and activated. Activated MLKL gets oligomerized and disrupts the cytomembrane, ultimately culminating in cell death. Top right: the initiation of pyroptosis includes two ways. Canonical pyroptosis is induced by the binding of the pattern recognition receptor (PPR) and its corresponding adaptor, which leads to the activation of caspase-1. Caspase-1 then cleaves gasdermin D (GSDMD), IL-1β, and IL-18. Noncanonical pyroptosis is mediated by lipopolysaccharide (LPS)-activated caspase-4/5/11, which also cleaves GSDMD. NH₂-terminal domain of GSDMD (GSDMD-N) gets oligomerized and generates pores in the cytomembrane, resulting in IL-1β and IL-18 leakage and cell death. Bottom left: ferroptosis is executed by overwhelming lipid peroxidation, which is catalyzed by ferritinophagy-induced free iron and lipoxygenase (LOX). The lethal lipid peroxidation can be inhibited by glutathione peroxidase 4 (GPX4) together with GSH. Bottom right: mitochondrial permeability transition (MPT)-mediated necrosis is characterized by generation of the MPT pore (MPTP), which disrupts the inner mitochondrial membrane (IMM) and allows the passage of small solutes [molecular weight (MW) < 1.5 kDa]. The formation of the MPTP is usually induced by increased calcium concentration or oxidant stress, and the MPTP can be inhibited by cyclosporine A (CsA), a potent antagonist of cyclophilin D (Cyp-D). NCOA4, nuclear receptor coactivator 4.