Fig. 3

Ischemia and reperfusion mediate multiple pathways of cell death. Ischemia and reperfusion mediate multiple pathways of cell death. Necrosis: hypoxia/ischemia induces glycolysis and activates plasma membrane sodium proton exchangers (NHE) to promote Na⁺-H⁺ exchange, thus increasing intracellular Na⁺. Increased Ca²⁺ concentration in the mitochondrial matrix promotes rupture of the outer mitochondrial membrane (OMM) and ultimately necrosis. Pyroptosis: activated Caspase-1 hydrolyzes GSDMD to form functional GSDMD, which then aggregates in the plasma membrane to form pores. Mature IL-1β and IL-18 can be diffused into extracellular cells through this pore. Apoptosis: the triggering of apoptosis includes mitochondrial pathway and death receptor pathway. Bax and Bak polymerize to form a mitochondrial transmembrane pore, which induces the permeabilization of mitochondrial outer membrane (MOMP) and promotes the release of apoptosis-related soluble proteins, such as cytochrome c. Cytochrome c binds Apaf-1 to promote the formation of apoptosome, which in turn activates caspase-9 and its downstream caspase-3, triggering cell apoptosis.²⁸⁴ Necroptosis: binding of the death receptor and ligand promotes the interaction of RIPK1 and RIPK3, resulting in phosphorylation of PIPK3 and subsequent phosphorylation of the pseudokinase MLKL. Phosphorylated MLKL translocates to the plasma membrane, leading to membrane infiltration and triggering necroptosis. Ferroptosis: three cellular pathways are known to inhibit ferroptosis mediated by lipid peroxidation, including GSH/GPX4, FSP1/CoQ10, and DHFR/BH4. These three pathways require the participation of NAD(P)H. NADPH is the substrate of NADPH oxidase (NOX). Activated NOX positively regulates ferroptosis through production of ROS. Fe²⁺ overload could produce Fe³⁺ by Fenton reaction. Ferroptosis is triggered by Fe³⁺ through activation of lipoxygenase or inactivation of glutathione peroxidase (GPX4). GPX4 requires the participation of System X_c^-. System X_c^- is a cystine/glutamate antiporter that promotes the entry of Cystine into cells. Cystine is then converted to cysteine, which produces glutathione (GSH). GSH is a cofactor of GPX4, which produces GPX4 with the participation of NADPH