Fig. 1: Schema of signaling pathways of cell death.

Apoptosis is carried out by regulated mechanisms triggered by various stress signals through the intrinsic pathway, and death receptors via the extrinsic pathway. In the intrinsic pathway, cytochrome-C is released from the mitochondrial intermembrane space, leading to the activation of caspase-9. In the extrinsic pathway, ligand binding to death receptors triggers the activation of caspase-8 and -10. Initiator caspases (caspases-9, -8, and -10) activate effector caspases, such as caspases-3 and -7, which carry out the controlled, energy-dependent dismantling of the cell. Apoptosis is characterized by cell shrinkage and membrane blebbing, followed by the formation of apoptotic bodies. These apoptotic bodies are typically engulfed by efferocytes or neighboring cells, preventing the release of damage-associated molecular patterns (DAMPs) and minimizing inflammation. Necroptosis is a form of regulated necrosis, which is activated by the necrosome containing Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 (after stimulation of death receptors). Necrosome activates mixed lineage kinase domain-like protein (MLKL) by phosphorylation, which results in its oligomerization and translocation to the plasma membrane. MLKL pores compromise membrane integrity, allowing an increased influx of cations, leading to osmotic imbalance. This imbalance causes cell swelling, membrane rupture, and the subsequent release of DAMPs into the extracellular space. During pyroptosis, caspases—primarily caspase-1, which is activated by NOD-like receptors (NLR) organized inflammasomes, or by caspases-4/5 (homologous to caspase-11 in mice), which are activated by lipopolysaccharide (LPS)—cleave gasdermin proteins to initiate cell death. The ASC adapter protein also promotes the activation of caspase-1 upon various stimuli. After the cleavage of gasdermin proteins their N-terminal domains oligomerize and create pores in the plasma membrane leading to cell death. These pores are not ion-selective, thus do not lead to osmotic shock. Additionally, activated caspase-1 cleaves the pro-forms of the inflammatory cytokines IL-1β and IL-18 into their mature forms, facilitating their release. Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation. It can occur due to increased ROS levels (which may be a consequence of iron-mediated Fenton reactions) or a reduced capacity of the cell’s antioxidant system. The oxidation of phospholipids containing polyunsaturated fatty acids increases lipid peroxide levels, leading to enhanced membrane permeability and potential rupture. The oxidative balance of the cells is maintained by the cooperation of the xCT transporter and glutathione peroxidase 4 (GPx4). xCT ensures the transport of cysteine, a glutathione precursor, into the cell, while GPx4 protects cells from oxidative stress by catalyzing the reduction of lipids and other organic hydroperoxides to their corresponding alcohol forms, using glutathione as a substrate. Parthanatos is initiated by hyperactivation of PARP1, a key enzyme in the DNA damage response, leading to depletion of the PARP substrates NAD+ and ATP. As a result, the cells’ energy source is exhausted. In addition to cellular energy deficiency, cell death is accompanied by the release of apoptosis-inducing factor (AIF) from the mitochondria, which is translocated to the nucleus after parylation by the PARP enzyme and induces Macrophage migration inhibitory factor (MIF)-dependent DNA fragmentation. Activation of mitochondrial permeability transition (MPT) is a consequence of intracellular stress signals that lead to dysregulation of the inner mitochondrial membrane. This can cause osmotic rupture of both mitochondrial membranes, resulting in cyclophilin D (CYPD)-dependent necrosis. CYPD in conjunction with a voltage dependent anion channel (VDAC) and adenine-nucleotide translocase (ANT) forms the permeability transition pore complex. Under oxidative stress, low ATP levels, or high Ca2+ concentrations, this complex forms open pores between the inner and outer mitochondrial membranes. This results in mitochondrial swelling and allows unregulated diffusion of molecules, ions and apoptogenic proteins. For a deeper understanding of signaling pathways, we recommend the review of the Cell Death Nomenclature Committee [4]. Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), Apoptosis-inducing factor mitochondria associated 1 (AIF), Cyclophilin D (CyPD), cystine/glutamate antiporter (xCT), damage–associated molecular pattern (DAMP), Gasdermin (GSDM), glutathione GSH, glutathione peroxidase (GPx4), inner mitochondrial membrane (IMM), Macrophage migration inhibitory factor (MIF), mitochondrial permeability transition (MPT), Mixed lineage kinase domain-like protein (MLKL), NOD-like receptor (NLR), oxidized glutathione (GSSG), pattern recognition receptor (PRR), Poly(ADP-ribose) polymerase 1 (PARP-1), Receptor-interacting serine/threonine-protein kinase 1 (RIPK1), reactive oxygen species (ROS).