Cell death is essential for development, growth, and survival, aiding tissue remodeling and homeostasis by removing unwanted or harmful cells. Key programmed forms include apoptosis, necroptosis, and pyroptosis, each modulating immune responses differently—apoptosis suppresses immunity, while necroptosis and pyroptosis amplify it via inflammation. Proper regulation is vital; insufficient cell death contributes to cancer, infections, and autoimmunity, whereas excessive death drives degenerative and inflammatory diseases. Understanding the regulation and activation of cell death during disease is crucial for therapeutic strategies.
Intrinsic Apoptosis
The intrinsic (mitochondrial) apoptosis pathway is activated by stresses such as DNA damage, oncogene activation, or growth factor deprivation. These stresses alter the balance between pro- and anti-apoptotic members of the BCL-2 protein family, all containing BH domains. Pro-apoptotic BH3-only proteins (e.g., BAD, BIM, PUMA) are unleashed, binding to and neutralizing anti-apoptotic relatives (e.g., BCL-2, MCL-1, BCL-XL). This releases pro-apoptotic effectors BAX and BAK from inhibition, allowing them to oligomerize and permeabilize the mitochondrial outer membrane. Some BH3-only proteins neutralize all anti-apoptotic members, while others are selective. Certain BH3-only proteins, like BIM, may also directly activate BAX and BAK.
Extrinsic Apoptosis and Necroptosis
Extrinsic apoptosis is an alternative pathway to activate caspase-3 and -7, mediated by caspase-8. It is triggered by death ligands binding to death receptors on the cell surface. Ligand-receptor pairs include FASL with FAS, TNF with TNF-R1, and TRAIL with TRAIL-R1/R2 (mice have only one TRAIL receptor). Although called death receptors, these receptors don’t exclusively signal cell death. Many cells activated by TNF-R1 respond by activating NF-κB and increasing proinflammatory gene expression, not by dying. Other perturbations are needed for TNF-induced cell death in these cells.
Pyroptosis
Pyroptosis describes cell death mediated by pores formed in the plasma membrane by gasdermin family proteins (e.g., GSDMD, GSDME). This lytic death, observed in various cell types, often involves cell swelling and bursting (plasma membrane rupture). This rupture releases pro-inflammatory intracellular molecules (DAMPs), triggering innate immune responses in neighboring cells. GSDMD-dependent pyroptosis helps clear intracellular bacteria like Salmonella, though some pathogens, such as Shigella, can evade this by degrading gasdermins. Pyroptosis is triggered when upstream mechanisms, including inflammasome activation, cleave gasdermins (primarily GSDMD), releasing their N-terminal pore-forming domain. Canonical inflammasomes activate caspase-1, while non-canonical inflammasomes activate caspase-4/5/11 (or mouse caspase-11). These caspases cleave GSDMD, inducing pyroptosis. Caspase-1 also cleaves pro-IL-1β and pro-IL-18 into active cytokines. The release of IL-1β, a potent pyrogen, makes pyroptosis a highly pro-inflammatory form of cell death. Note that non-canonical inflammasome activation can indirectly activate the NLRP3 inflammasome and caspase-1[1].
Autophagy
Autophagy is a cellular process for degrading and recycling proteins and organelles to maintain homeostasis. While generally protective, disrupted or excessive autophagy often leads to cell death. Despite recent advances, key questions remain about how autophagy regulates cell death and the mechanisms of autophagy-dependent (ADCD) and autophagy-mediated cell death (AMCD). This article highlights autophagy’s diverse roles in cell death, focusing on six main autophagy-related cell death modalities, including metabolic changes in ER-phagy-induced death and mitophagy’s role in autophagy-mediated ferroptosis. Finally, it discusses enhancing autophagy for disease treatment and proposes using autophagy’s functional conversions for tumor therapy[2].
Ferroptosis
Ferroptosis is a recently discovered form of cell death characterized by iron accumulation and lipid peroxidation. It is iron-dependent and occurs when factors reduce cellular antioxidant capacity, often by inhibiting glutathione peroxidase, leading to lipid ROS accumulation and oxidative cell death. Ferroptosis is increasingly recognized as playing a role in various disease pathologies, including cancer, neurodegenerative diseases, ischemia-reperfusion injury, kidney injury, and blood disorders. Consequently, modulating ferroptosis for therapeutic intervention is a major focus of research. However, further exploration is needed to fully understand its functional roles and specific molecular mechanisms to develop effective treatments. This review summarizes recent ferroptosis research, aiming to enhance understanding of its pathogenesis and identify potential therapeutic targets[3].
