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Programmed cell death

Programmed cell death (PCD) is a genetically regulated process of cellular self-destruction that eliminates superfluous, damaged, or infected cells in a controlled manner, distinct from accidental cell death like necrosis.^[1] First described in the 1960s, PCD is essential for embryonic development, tissue homeostasis, and immune regulation in multicellular organisms, where it prevents inflammation by allowing orderly dismantling and phagocytosis of dying cells without releasing harmful contents.^[2] PCD encompasses multiple interconnected forms, each with specific morphological and biochemical features. The classical type, apoptosis, involves caspase activation, chromatin condensation, DNA fragmentation, and cell shrinkage, executed via intrinsic (mitochondrial) or extrinsic (death receptor) pathways to maintain tissue balance and remove unnecessary cells during development—such as sculpting digits in vertebrate limbs or eliminating up to half of nascent neurons in the nervous system.^[2]^[1] Other forms include necroptosis, a caspase-independent inflammatory process driven by RIPK1/RIPK3/MLKL kinases forming membrane pores; pyroptosis, mediated by gasdermin pores and inflammasomes for pathogen clearance; ferroptosis, an iron-dependent lipid peroxidation pathway; cuproptosis, a copper-dependent form involving mitochondrial protein-lipidation; and autophagy-dependent cell death, involving lysosomal degradation for stress responses.^[3]^[1] These pathways often interconvert, such as apoptosis shifting to pyroptosis under certain conditions, highlighting PCD's dynamic regulation by genes and proteins like Bcl-2 family members and caspases.^[3] Dysregulation of PCD underlies numerous diseases, making it a key therapeutic target. In cancer, evasion of apoptosis promotes tumor survival, while excessive PCD contributes to neurodegenerative disorders like Alzheimer's through neuronal loss; conversely, boosting PCD can enhance anti-tumor immunity.^[1] In autoimmune and inflammatory conditions, such as inflammatory bowel disease, overactive necroptosis or pyroptosis amplifies tissue damage via cytokine release.^[3] Ongoing research, including clinical trials targeting PCD modulators, underscores its role in balancing life, death, and disease across organisms.^[1]

Fundamentals

Definition and Characteristics

Programmed cell death (PCD) is an active, genetically regulated process that orchestrates the controlled elimination of cells, often described as cellular suicide, essential for maintaining organismal homeostasis and development.^[4] Unlike accidental cell death, such as necrosis, which is a passive, uncontrolled response to severe injury resulting in rapid cell lysis and inflammation, PCD is energy-dependent and typically non-inflammatory, ensuring orderly dismantling without the release of intracellular contents that could provoke immune responses.^[5] This distinction was first highlighted in the seminal description of apoptosis as a distinct mode of cell death by Kerr, Wyllie, and Currie in 1972.^[6] Key characteristics of PCD include its reliance on ATP for execution, activation of specific proteases like caspases (particularly in apoptosis), DNA fragmentation into nucleosomal units, and systematic cellular disassembly that preserves membrane integrity in early stages.^[4] Morphologically, PCD manifests through cell shrinkage, nuclear chromatin condensation (pyknosis), plasma membrane blebbing, and the formation of apoptotic bodies in apoptosis, while autophagy features the sequestration of cytoplasmic components into double-membrane autophagosomes.^[5] In regulated necrosis, such as necroptosis, cells exhibit swelling and eventual plasma membrane rupture, bridging controlled and uncontrolled death forms.^[3] Biochemically, PCD is marked by the externalization of phosphatidylserine on the outer leaflet of the plasma membrane, signaling for phagocytic clearance; release of cytochrome c from mitochondria, which initiates caspase cascades in apoptosis; and cleavage of poly(ADP-ribose) polymerase (PARP), a key indicator of caspase activity that halts DNA repair and facilitates cell death.^[5] These hallmarks enable precise detection and underscore PCD's role as a deliberate, non-random event. Major forms of PCD encompass apoptosis, the classic caspase-dependent process with anti-inflammatory outcomes; autophagy, a degradative pathway involving lysosomal fusion that can promote survival or lead to cell death; and regulated necrosis, including necroptosis and pyroptosis, which are lytic yet genetically controlled and often pro-inflammatory.^[3]

Historical Development

The earliest observations of programmed cell death (PCD) date back to the 19th century, when German anatomist Carl Vogt described the resorption of the tadpole tail during amphibian metamorphosis in 1842, noting the organized elimination of cells as a normal developmental process rather than pathological decay.^[7] Vogt's work, based on microscopic examinations of toad embryos, highlighted spontaneous cell death in tissues like the notochord and cartilage, laying foundational insights into physiological cell elimination long before the cell theory was fully established.^[8] These early reports emphasized cell death as an integral part of embryogenesis, though the mechanisms remained unexplored for over a century. In the mid-20th century, research shifted toward distinguishing controlled cell death from accidental necrosis, with studies in the 1960s identifying "shrinkage necrosis" in various tissues.^[9] A pivotal moment came in 1972, when John F.R. Kerr, Andrew H. Wyllie, and Alastair R. Currie coined the term "apoptosis" to describe a distinct morphological pattern of cell death observed in glucocorticoid-treated rat thymocytes and other models, characterized by cell shrinkage, chromatin condensation, and rapid phagocytosis without inflammation. This nomenclature, derived from the Greek word for "falling off" like leaves, marked apoptosis as a fundamental biological process involved in tissue homeostasis and development, fundamentally differentiating it from necrotic cell lysis.^[10] The 1980s and 1990s brought genetic insights through studies in the nematode Caenorhabditis elegans, where Robert Horvitz and colleagues identified key genes regulating PCD. In 1986, mutations in ced-3 and ced-4 were shown to block nearly all programmed cell deaths during C. elegans development, establishing these as essential components of the death machinery.^[11] Horvitz's work, which earned him the 2002 Nobel Prize in Physiology or Medicine shared with Sydney Brenner and John Sulston, linked PCD to genetic control and revealed ced-3 as a cysteine protease homolog (caspase) in 1993.^[12] Concurrently, the 1988 discovery of the bcl-2 gene by David Vaux, Suzanne Cory, and Jerry Adams demonstrated its role in suppressing apoptosis in hematopoietic cells, transforming bcl-2 from an oncogene identified in lymphomas into a key anti-death regulator.^[13] By the 1990s, the broader term "programmed cell death" emerged to encompass apoptosis and other genetically orchestrated forms beyond necrosis, reflecting the field's expansion from "physiological cell death" used in earlier literature.^[14] This terminological shift, formalized in nomenclature guidelines, accommodated discoveries like regulated necrosis (necroptosis) in the 2000s and non-apoptotic pathways. Yoshinori Ohsumi's identification of autophagy genes (ATG) in yeast during the 1990s, recognized by the 2016 Nobel Prize, revealed autophagy's role in PCD as a degradative, self-eating process distinct from apoptosis.^[15] These advances integrated PCD into cancer research and beyond, highlighting its evolutionary conservation and diverse forms.^[16]

Types

Apoptosis

Apoptosis is the canonical form of programmed cell death (PCD), characterized as a caspase-dependent, non-lytic process that enables the precise elimination of cells while maintaining tissue integrity and homeostasis.^[17] This regulated mechanism contrasts with uncontrolled cell death by orchestrating cellular dismantling through enzymatic activation, preventing the release of intracellular contents that could trigger inflammation.^[18] Essential for development, differentiation, and the removal of damaged or superfluous cells, apoptosis ensures balanced cell populations across multicellular organisms.^[19] Key features of apoptosis include its rapid execution, typically completing within hours, which allows for swift tissue remodeling without prolonged disruption.^[20] During this process, the cell shrinks, the plasma membrane blebs to form sealed apoptotic bodies containing fragmented organelles and nuclear material, which are subsequently phagocytosed by neighboring cells or professional phagocytes.^[21] This containment mechanism renders apoptosis inherently anti-inflammatory, as it avoids spillage of damage-associated molecular patterns (DAMPs) that would otherwise provoke immune responses.^[22] Apoptosis can be initiated via extrinsic pathways involving death receptors or intrinsic pathways sensing cellular stress, both converging on caspase activation.^[17] Major regulators of apoptosis include the Bcl-2 family proteins, which balance pro-apoptotic and anti-apoptotic signals at the mitochondrial outer membrane. Pro-apoptotic members such as Bax, Bak, and Bid promote mitochondrial outer membrane permeabilization (MOMP) to release cytochrome c, initiating the caspase cascade, while anti-apoptotic counterparts like Bcl-2 inhibit this process.^[23] Inhibitors of apoptosis proteins (IAPs), such as XIAP, further suppress execution by directly binding and inhibiting caspases, thereby fine-tuning the apoptotic threshold.^[24] Morphologically, apoptosis features chromatin condensation and nuclear fragmentation into nucleosomal units, resulting in a characteristic DNA ladder of 180-200 base pair multiples detectable by gel electrophoresis.^[25] Biochemically, the externalization of phosphatidylserine (PS) from the inner to the outer plasma membrane leaflet serves as an "eat-me" signal, facilitating recognition and engulfment by phagocytes to ensure non-inflammatory clearance.^[26] Apoptosis is evolutionarily conserved from nematodes, such as Caenorhabditis elegans, to mammals, underscoring its fundamental role in metazoan biology.^[27] In vertebrates, it is exemplified by interdigital cell death during limb development, where apoptosis sculpts individual digits from the embryonic paddle by eliminating webbing tissue.^[28] Unlike autophagy, which primarily serves survival by recycling cellular components under stress, or necrosis, which is lytic and pro-inflammatory due to membrane rupture, apoptosis provides a controlled, non-inflammatory route for cell elimination.^[29]

Autophagy

Autophagy is a conserved cellular process characterized by the sequestration of cytoplasmic components into double-membrane vesicles called autophagosomes, which subsequently fuse with lysosomes to facilitate the bulk degradation and recycling of cellular materials.^[30] This "self-eating" mechanism primarily serves a prosurvival role by maintaining homeostasis under stress, but excessive activation can lead to autophagic cell death, a form of programmed cell death (PCD) where degradation overwhelms cellular viability.^[30] Autophagy encompasses three main types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA), with macroautophagy representing the predominant pathway implicated in PCD.^[31] In macroautophagy, cytoplasmic cargo is nonselectively or selectively engulfed by autophagosomes for lysosomal delivery, whereas microautophagy involves direct invagination of lysosomal membranes to uptake small portions of cytoplasm, and CMA targets specific proteins via chaperone recognition of a KFERQ-like motif for lysosomal import.^[31] Macroautophagy is the primary form associated with PCD due to its capacity for large-scale degradation.^[30] Central to macroautophagy are autophagy-related (Atg) proteins, first identified in yeast, which orchestrate autophagosome formation through a hierarchical assembly. Key players include Atg1 (ULK1 in mammals), a serine/threonine kinase that initiates the process, and Atg8 (LC3 in mammals), which lipidates to phosphatidylethanolamine to anchor the autophagosomal membrane. Initiation is regulated by phosphatidylinositol 3-kinase (PI3K) signaling, particularly the class III PI3K (Vps34) complex, which generates phosphatidylinositol 3-phosphate to recruit Atg effectors like Atg18/WIPI2 for membrane nucleation and expansion.^[30] Common triggers of autophagy include nutrient starvation, which activates the process via inhibition of mechanistic target of rapamycin (mTOR) and subsequent ULK1 dephosphorylation, and endoplasmic reticulum (ER) stress, mediated by the unfolded protein response (UPR) pathways involving ATF4 and IRE1 to alleviate protein misfolding.^[32]^[33] When these stressors persist, hyperactivation leads to autophagic cell death, characterized by unchecked lysosomal degradation that disrupts essential cellular structures and ion homeostasis.^[30] Morphological hallmarks of autophagic cell death include cytoplasmic vacuolization, accumulation of autophagic vacuoles, and perinuclear swelling, often without plasma membrane rupture, distinguishing it from necrotic forms.^[30] Unlike apoptosis (Type I PCD), which relies on caspase activation for orderly dismantling, autophagy is classified as Type II PCD due to its dependence on lysosomal degradation and Atg machinery, though it is less frequently a direct death executor and more often a modulator.^[34] In early tumorigenesis, autophagy exerts a suppressive effect by clearing damaged organelles, reducing reactive oxygen species, and preventing genomic instability, thereby inhibiting malignant transformation.^[30]

Regulated Necrosis

Regulated necrosis encompasses a family of programmed cell death (PCD) modalities that exhibit lytic morphology, characterized by plasma membrane rupture and the release of damage-associated molecular patterns (DAMPs), which trigger robust inflammatory responses as an alternative to the non-inflammatory clearance seen in apoptosis.^[35] Unlike accidental necrosis, these processes are genetically controlled and can bypass apoptosis when caspase activity is inhibited, serving as a backup mechanism for cell elimination under stress conditions such as pathogen invasion or metabolic dysregulation.^[36] This form of PCD, often termed Type III PCD, contrasts with Type I (apoptosis) and Type II (autophagy) by promoting inflammation to alert the immune system, though excessive activation contributes to tissue damage in diseases like ischemia-reperfusion injury.^[37] Necroptosis represents a prototypical regulated necrosis pathway, dependent on the sequential activation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL), typically triggered by tumor necrosis factor (TNF) signaling when caspases are blocked.^[38] Hallmarks include cellular swelling, organelle dilation, and eventual membrane rupture, leading to the release of intracellular contents that amplify inflammation via DAMP signaling.^[35] This pathway shares extrinsic triggers like TNF with apoptosis but diverges into a lytic fate upon caspase inhibition, highlighting its role as a fail-safe mechanism.^[37] Ferroptosis is an iron-dependent form of regulated necrosis driven by the accumulation of lipid peroxides in cellular membranes, primarily due to inhibition or depletion of glutathione peroxidase 4 (GPX4), the key enzyme neutralizing phospholipid hydroperoxides.^[39] Morphologically, it features shrunken mitochondria with condensed membrane densities but lacks nuclear fragmentation or apoptotic blebbing, distinguishing it from other PCD types.^[39] The process relies on labile iron pools catalyzing Fenton reactions to propagate oxidative damage, resulting in DAMP release and proinflammatory signaling.^[39] Other variants include pyroptosis, an inflammasome-mediated process involving caspase-1 activation that cleaves gasdermin D to form plasma membrane pores, causing osmotic cell lysis and interleukin-1β/18 release to drive acute inflammation.^[40] Parthanatos, meanwhile, arises from poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation in response to DNA damage, leading to ATP depletion and translocation of apoptosis-inducing factor (AIF) to the nucleus for caspase-independent chromatinolysis and necrosis.^[19] These pathways exemplify the diversity of regulated necrosis, each tailored to specific stressors like infection or genotoxicity. As Type III PCD, regulated necrosis emerged as a recognized entity in the early 2000s through studies on RIPK-dependent cell death, expanding the PCD paradigm beyond non-lytic forms to include these inflammatory lytic alternatives.^[36] Physiologically, it bolsters pathogen defense by eliminating infected cells and stimulating immunity, as seen in necroptosis's antiviral and antibacterial roles.^[35] Pathologically, however, it exacerbates conditions like ischemia, where RIPK3/MLKL activation in hypoxic tissues promotes excessive inflammation and organ failure.^[41] In distinction from apoptosis's anti-inflammatory profile—where engulfed corpses suppress immune activation—regulated necrosis is inherently pro-inflammatory, with membrane rupture exposing DAMPs to pattern recognition receptors, thereby recruiting neutrophils and amplifying cytokine storms in contexts like infection or autoimmunity.^[35] This proinflammatory bias positions regulated necrosis as a double-edged sword, essential for host protection yet detrimental when dysregulated.^[37]

Other Forms

Beyond the core forms of programmed cell death (PCD), several context-specific variants highlight the diversity of cellular suicide mechanisms, often triggered by unique environmental cues or cellular stresses. These include anoikis, which enforces tissue integrity in anchorage-dependent cells; mitotic catastrophe, arising from failed cell division; entosis, involving homotypic cell engulfment; paraptosis, characterized by organelle swelling; and hybrid or emerging types like aponecrosis and cuproptosis. These processes underscore PCD's adaptability, frequently serving as fallback or specialized responses in multicellular organisms, particularly in epithelial or proliferative contexts.^[42] Anoikis represents a specialized apoptotic response initiated by the detachment of adherent cells from the extracellular matrix (ECM), preventing survival of displaced cells that could otherwise contribute to pathological conditions like metastasis. This form of PCD is mediated through disrupted integrin-ECM interactions, which activate intrinsic apoptotic pathways involving mitochondrial dysfunction and caspase activation. In epithelial cells, anoikis maintains tissue architecture by eliminating cells that lose proper anchorage, such as during normal turnover in the gut or skin. Resistance to anoikis is a hallmark of metastatic cancer cells, allowing them to survive in suspension or foreign environments.^[43]^[44]^[45] Mitotic catastrophe occurs when cells enter mitosis with irreparable damage, such as DNA double-strand breaks, leading to aberrant chromosome segregation and subsequent cell demise. Unlike classical apoptosis, it manifests as prolonged mitotic arrest followed by features resembling apoptosis, including chromatin condensation, or senescence with multinucleation and cytoplasmic bridges. This process is often triggered by genotoxic agents or spindle poisons in p53-deficient cells, where it acts as a safeguard against propagation of genomic instability. In cancer therapy, inducing mitotic catastrophe enhances tumor cell elimination without relying solely on apoptotic executioners.^[46]^[47] Entosis is a non-apoptotic PCD driven by homotypic cell adhesion and actomyosin contractility, where one cell invades and is internalized by a neighboring cell, culminating in lysosomal degradation of the engulfed cell. This cell-in-cell structure formation is promoted by loss of ECM attachment or glucose deprivation, common in crowded tumor microenvironments, and is regulated by adherens junctions and Rho GTPases. Unlike phagocytosis, entosis involves live cell engulfment without prior death signals, and the internalized cell often dies via autophagy-like vacuolization. In epithelial tissues, entosis contributes to cellular competition and tumor suppression by selectively eliminating weaker cells.^[48] Paraptosis emerges as a caspase-independent PCD pathway featuring extensive cytoplasmic vacuolization due to swelling of mitochondria and endoplasmic reticulum, distinct from apoptotic blebbing or necrotic rupture. Initially identified through overexpression of the insulin-like growth factor-1 receptor (IGF-1R) in fibroblasts, it involves MAP kinase signaling, particularly JNK activation, and is inhibited by Alix/AIP1. This form lacks DNA fragmentation but relies on protein synthesis and ER stress responses. In cancer cells, paraptosis can be induced by certain chemotherapeutics, offering a therapeutic avenue for apoptosis-resistant tumors.^[49]^[50] Hybrid forms like aponecrosis blend apoptotic and necrotic traits, initiating with caspase-dependent features such as phosphatidylserine exposure but progressing to membrane lysis and inflammation when apoptosis is incomplete. This syncretic death is observed under severe stress, like hypoxia or toxin exposure, where early apoptotic signals fail to execute fully. Emerging variants include cuproptosis, a copper-dependent PCD discovered in 2022, where excess copper binds lipoylated tricarboxylic acid cycle proteins, causing proteotoxic stress and mitochondrial collapse without caspase involvement. These hybrids illustrate PCD's continuum, often defaulting to apoptotic-like outcomes in permissive contexts.^[51]^[52] PANoptosis is an inflammatory programmed cell death pathway defined in 2023 that uniquely combines features of pyroptosis, apoptosis, and necroptosis (hence "PAN"), mediated by the PANoptosome—a multiprotein complex assembled in response to innate immune sensors like Toll-like receptors or cytokine receptors. Triggered by microbial infections, sterile inflammation, or cancer-related signals, it involves concurrent activation of caspases (caspase-1/8), RIPK3/MLKL, and other effectors, leading to lytic cell death, gasdermin pore formation, and release of inflammatory cytokines such as IL-1β. Unlike individual pathways, PANoptosis cannot be fully inhibited by blocking a single modality, highlighting its integrated nature. As of 2025, it plays key roles in antitumor immunity, pathogen defense, and diseases including cancer and neurological disorders.^[53]

Mechanisms

Extrinsic Pathways

The extrinsic pathways of programmed cell death (PCD) are initiated by external signals that bind to specific transmembrane death receptors on the cell surface, primarily triggering apoptosis and, under certain conditions, necroptosis. These pathways are distinct from intrinsic mechanisms as they rely on ligand-receptor interactions rather than internal cellular stress. Key death receptors belong to the tumor necrosis factor receptor (TNFR) superfamily and include TNFR1, Fas (also known as CD95), and TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5).^[54]^[55] Their cognate ligands—such as tumor necrosis factor-α (TNF-α) for TNFR1, Fas ligand (FasL) for Fas, and TNF-related apoptosis-inducing ligand (TRAIL) for TRAIL receptors—bind to induce receptor trimerization and downstream signaling.^[54]^[55] Upon ligand binding, the death-inducing signaling complex (DISC) assembles at the cytoplasmic death domain (DD) of the receptor. For Fas and TRAIL receptors, the adaptor protein Fas-associated death domain (FADD) is recruited via DD-DD interactions, followed by the binding of procaspase-8 (and procaspase-10) through death effector domain (DED) interactions; TNFR1 signaling involves an additional adaptor, TNFR-associated death domain (TRADD), before FADD recruitment.^[55]^[54] Within the DISC, procaspase-8 undergoes induced proximity and dimerization, leading to its autocleavage into active caspase-8 (p18/p10 subunits). Active caspase-8 then directly cleaves and activates effector caspases, such as caspase-3 and -7, which execute apoptosis by dismantling cellular structures.^[55]^[54] The extrinsic pathway can bifurcate toward necroptosis when caspase-8 activity is inhibited (e.g., by viral proteins or pharmacological blockers like z-VAD-fmk). In this scenario, receptor-interacting protein kinase 1 (RIPK1) and RIPK3 form the necrosome through RIP homotypic interaction motif (RHIM)-mediated interactions, with FADD serving as a scaffold. RIPK3 phosphorylates mixed lineage kinase domain-like protein (MLKL) at residues Thr357 and Ser358, inducing MLKL oligomerization and translocation to the plasma membrane, where it forms pores that disrupt membrane integrity and trigger lytic cell death.^[56]^[55] In autophagy, the extrinsic pathways play a limited role, primarily through TNF-α signaling in NF-κB-deficient contexts, where it upregulates Beclin-1 expression via reactive oxygen species (ROS), promoting autophagosome formation and potentially amplifying apoptosis.^[57] Caspase-8 from the extrinsic cascade can also briefly amplify intrinsic signaling by cleaving Bid into truncated Bid (tBid), which translocates to mitochondria.^[54]

Intrinsic Pathways

The intrinsic pathway of programmed cell death represents an internal stress-responsive mechanism that primarily converges on mitochondria to trigger cell demise, distinguishing it from ligand-mediated routes by its reliance on intracellular damage signals. This pathway is central to apoptosis and shares elements with other regulated death modalities, initiating through sensors of cellular perturbations that ultimately perturb mitochondrial integrity.^[58] Common triggers include DNA damage, endoplasmic reticulum (ER) stress, and growth factor deprivation, which collectively destabilize cellular homeostasis and activate pro-death signaling. In particular, the tumor suppressor protein p53 responds to genotoxic insults like DNA double-strand breaks by acting as a transcription factor, upregulating BH3-only proteins such as Puma and Noxa to promote mitochondrial outer membrane permeabilization (MOMP). This p53-dependent transcriptional program ensures the elimination of potentially oncogenic cells bearing irreparable damage.^[59] Regulation of the intrinsic pathway hinges on the Bcl-2 family of proteins, which orchestrate a delicate balance between survival and death at the mitochondria. Pro-apoptotic BH3-only activators, including Bim and Puma, initiate the process by directly engaging and activating effector proteins Bax and Bak, inducing their conformational change and oligomerization to form pores in the outer mitochondrial membrane. Conversely, anti-apoptotic members such as Bcl-2 and Mcl-1 counteract this by sequestering BH3-only activators or directly binding Bax/Bak to inhibit pore formation, thereby preserving mitochondrial function under mild stress. The net outcome depends on the stoichiometric interplay among these proteins, with activators tipping the scale toward commitment to death.^[60]^[61] A pivotal event in the pathway is MOMP, mediated by Bax/Bak oligomers, which releases intermembrane space proteins like cytochrome c into the cytosol. Cytochrome c then oligomerizes with Apaf-1 and procaspase-9 to assemble the apoptosome, a wheel-like complex that autoactivates caspase-9 and amplifies the proteolytic cascade leading to cell dismantling. Beyond apoptosis, intrinsic signals can intersect with autophagy through mitophagy, where damaged mitochondria are selectively degraded; here, PINK1 stabilizes on depolarized organelles to phosphorylate and recruit the E3 ubiquitin ligase Parkin, which tags mitochondrial components for autophagosomal engulfment and lysosomal clearance, preventing excessive ROS accumulation that might otherwise escalate to death.^[62]^[63] In ferroptosis, an iron-catalyzed form of regulated necrosis, intrinsic stressors drive lipid peroxidation independently of caspases, yet mitochondrial ROS production plays a critical amplifying role by fueling polyunsaturated fatty acid oxidation in membranes. This process, often initiated by glutathione peroxidase 4 (GPX4) inhibition, contrasts with apoptotic execution but underscores the mitochondria's role as a hub for diverse death outcomes under oxidative duress.^[64] The rheostat-like control by the Bcl-2 family offers therapeutic leverage, with BH3 mimetics emerging as targeted agents to disrupt anti-apoptotic dominance. For instance, venetoclax selectively binds Bcl-2's hydrophobic groove to displace pro-apoptotic effectors, restoring MOMP sensitivity in malignancies like chronic lymphocytic leukemia, where Bcl-2 overexpression confers resistance. These small molecules, inspired by BH3 domains, exemplify how modulating intrinsic pathway dynamics can selectively induce death in diseased cells while sparing healthy ones.^[65]

Executioner Mechanisms

In programmed cell death (PCD), executioner mechanisms represent the terminal phase where cellular dismantling occurs, shared across various forms despite differences in upstream signaling. In apoptosis, the primary executioners are effector caspases, particularly caspases-3, -6, and -7, which are activated by initiator caspases and subsequently cleave a wide array of cellular substrates to orchestrate morphological changes such as nuclear condensation, chromatin fragmentation, and membrane blebbing. Caspase-3, for instance, targets structural proteins like lamin A and B, leading to nuclear envelope breakdown, while also cleaving inhibitor of caspase-activated DNase (ICAD), thereby releasing the active DNase CAD to initiate DNA degradation. These effector caspases ensure a controlled, non-inflammatory disassembly, distinguishing apoptosis from lytic forms of PCD. DNA fragmentation is a hallmark of apoptotic execution, mediated by CAD (also known as DFF40), which, upon release from ICAD by caspase-3 cleavage, generates high-molecular-weight DNA fragments of 50-300 kb, corresponding to chromatin loop domains attached to the nuclear scaffold. Subsequent internucleosomal cleavage by CAD produces the characteristic 180-200 bp "laddering" pattern observable in gel electrophoresis, reflecting the spacing between nucleosomes and contributing to chromatin condensation. This process is tightly regulated to prevent premature DNA damage in healthy cells, with ICAD serving dual roles in inhibiting CAD activity and chaperoning its proper folding during synthesis. Phagocytic clearance is integral to apoptotic execution, preventing secondary necrosis and inflammation through exposure of "eat-me" signals and suppression of "don't-eat-me" signals. Phosphatidylserine (PS), normally confined to the inner plasma membrane leaflet, is externalized via caspase-dependent activation of phospholipid scramblases such as Xkr8 during apoptosis, serving as a key "eat-me" signal recognized by receptors such as TIM-4 and stabilin-2 on phagocytes.^[66] Concurrently, "don't-eat-me" signals like CD47, which binds SIRPα on macrophages to inhibit phagocytosis, are downregulated or overridden, ensuring efficient engulfment of apoptotic bodies. This rapid clearance mechanism maintains tissue homeostasis and suppresses pro-inflammatory responses. In non-apoptotic forms of PCD, executioner mechanisms diverge toward lytic outcomes. Pyroptosis is executed by gasdermin D (GSDMD), cleaved by inflammatory caspases-1 or -11, whose N-terminal fragment oligomerizes to form plasma membrane pores approximately 10-20 nm in diameter, leading to cell lysis and release of inflammatory contents like IL-1β. Similarly, in necroptosis, mixed lineage kinase domain-like (MLKL) is phosphorylated by RIPK3, prompting its oligomerization and translocation to the plasma membrane, where it forms cation-selective pores that disrupt ion homeostasis and cause membrane rupture. These pore-forming effectors contrast with apoptotic non-lytic dismantling but share the goal of eliminating compromised cells. Shared elements across PCD types include the regulated release of ATP and UTP from dying cells, which act as "find-me" signals to recruit phagocytes via P2Y2 receptors, occurring early in apoptosis without eliciting inflammation due to swift PS-mediated engulfment. In apoptosis, this rapid clearance by professional phagocytes like macrophages ensures immunologically silent removal, whereas delayed clearance in lytic PCD can promote inflammation. Cross-type integration is evident in caspase-independent pathways, such as autophagy, where Atg4 proteases cleave LC3/GABARAP family proteins to facilitate autophagosome formation, independent of effector caspases, though Atg4D can be cleaved by caspases during apoptosis to modulate mitochondrial targeting and link the processes.

Biological Roles

In Animal Development

Programmed cell death (PCD) is integral to animal development, enabling the precise sculpting of tissues and organs by eliminating superfluous cells while preserving homeostasis. In multicellular animals, PCD, primarily through apoptosis, facilitates morphogenesis by removing transient structures and refining cellular populations, ensuring proper organ formation and functional maturity. This process is tightly regulated and occurs in specific spatiotemporal patterns during embryogenesis and post-natal growth. During embryonic development, PCD plays a critical role in limb formation, particularly through interdigital apoptosis that separates digits. In vertebrates, the removal of mesenchymal tissue between developing digits via apoptosis is essential for free digit formation; this process is regulated by Hox genes, such as those in the HoxD cluster, which control the expression of pro-apoptotic factors like BMPs in the interdigital zones. Hox gene mutations can disrupt this apoptosis, leading to syndactyly, or webbed digits, as observed in mouse models where impaired interdigital cell death results in persistent tissue connections. Similarly, in other embryonic contexts, PCD eliminates vestigial structures, such as the tail in tadpole metamorphosis, contributing to species-specific body plans. In neurogenesis, PCD ensures the appropriate number and connectivity of neurons by eliminating excess cells generated during proliferation. Approximately 50-70% of newly generated neurons undergo PCD in the developing vertebrate nervous system, a process dependent on competition for limited neurotrophic factors like nerve growth factor (NGF), which promotes survival of select neurons while depriving others triggers apoptosis. This trophic factor-mediated selection refines neural circuits, as demonstrated in studies of sympathetic and sensory neurons where NGF deprivation activates caspase-dependent death pathways. Caspases, central to apoptotic execution, are briefly involved in this neuronal pruning, linking developmental PCD to core mechanisms. In the immune system, PCD is crucial for establishing self-tolerance through negative selection of autoreactive T cells in the thymus. Nearly all thymocytes whose T cell receptors bind strongly to self-antigens presented by thymic epithelial cells die via apoptosis, preventing autoimmunity by eliminating potentially harmful clones; overall, more than 95% of thymocytes undergo apoptosis during maturation. This process relies on signaling through the T cell receptor complex, activating intrinsic apoptotic pathways to delete high-affinity self-reactive cells. In invertebrate models like Caenorhabditis elegans, PCD is precisely programmed during development, providing insights into conserved mechanisms. In the C. elegans hermaphrodite, exactly 131 somatic cells, including those in the anterior pharynx, ventral nerve cord, and gonadal lineage, undergo PCD as part of normal development, executed by a core machinery involving ced-3 (caspase homolog) and ced-4 (Apaf-1 homolog). Mutants defective in these genes exhibit hyperplasia due to survival of cells fated to die, highlighting PCD's role in preventing overgrowth. Beyond development, PCD maintains tissue homeostasis in animals by regulating cell turnover. In epithelial tissues, such as the intestinal mucosa, apoptosis balances proliferation with shedding of senescent cells, ensuring barrier integrity and renewal without inflammation. Similarly, mature erythrocytes undergo an apoptosis-like PCD termed eryptosis, involving phosphatidylserine exposure and shrinkage, which signals macrophages for clearance from circulation, preventing accumulation of damaged cells. Defects in these homeostatic PCD processes, as seen in caspase-deficient mutants, lead to hyperplasia and tissue abnormalities, underscoring their necessity for balanced adult physiology.

In Plant and Fungal Systems

In plants, programmed cell death (PCD) plays essential roles in development, reproduction, and environmental adaptation, but differs fundamentally from animal apoptosis due to rigid cell walls that preclude phagocytosis and instead promote autolytic degradation of cellular contents in place.^[67]^[68] A prominent example is the hypersensitive response (HR), an apoptosis-like PCD activated upon pathogen recognition, where rapid cell death at infection sites, driven by reactive oxygen species (ROS) accumulation, confines pathogen spread and bolsters immunity.^[69]^[70] Similarly, under hypoxic stress from waterlogging, roots form lysigenous aerenchyma through targeted cortical cell PCD, creating intercellular air spaces for oxygen diffusion; this process is triggered by ethylene signaling following hypoxia-induced ROS and nitric oxide production.^[71]^[72]^[73] Reproductive processes in plants also rely on PCD for precise tissue remodeling. In self-incompatible species like Papaver rhoeas, incompatible pollen tubes undergo PCD upon pistil recognition, involving cytosolic acidification, DNA fragmentation, and actin depolymerization to halt self-fertilization and promote genetic diversity.^[74]^[75] Post-fertilization, the nucellus in seeds degenerates via PCD, a vacuole-mediated process that clears maternal tissue to facilitate endosperm expansion and nutrient allocation to the developing embryo, as observed in wheat and Arabidopsis.^[76]^[77] In vascular development, tracheary elements in xylem differentiate terminally through PCD, which removes protoplasts after secondary wall thickening, yielding hollow conduits for efficient water conduction; this autolytic PCD involves vacuolar collapse and nuclease activation without rapid cytoplasmic clearance.^[78]^[79]^[80] Central regulators of plant PCD include metacaspases, a family of cysteine proteases structurally related to animal caspases but with distinct substrate preferences, which execute death in developmental contexts like xylem formation and defense responses such as HR.^[81]^[82] Vacuolar processing enzymes (VPEs), legumain-type cysteine proteases, further drive PCD by autoactivating in acidic vacuoles, rupturing the tonoplast, and triggering proteolytic cascades that dismantle cellular structures during stress-induced or developmental death.^[83]^[84] Plant and fungal PCD share conserved autophagic mechanisms for organelle recycling, though adapted to sessile lifestyles.^[85] In fungal systems, PCD supports multicellular organization and resource management in mycelia and fruiting bodies. Hyphal compartments undergo PCD to facilitate nutrient allocation, particularly during carbon starvation, where older segments empty via autophagy, recycling materials to sustain apical growth and network foraging.^[86]^[87] Autophagic cell death predominates in aging mycelia, enabling survival under nutrient limitation by degrading unnecessary components; in species like Aspergillus niger and Podospora anserina, autophagy mutants exhibit accelerated senescence and reduced longevity, underscoring its role in stress adaptation.^[88]^[89] During fruiting body development and senescence, PCD sculpts the structure by eliminating non-sporulating hyphae, releasing nutrients to fuel spore maturation; this process, evident in basidiomycetes, involves compartmentalized autolysis similar to plant vascular PCD but without centralized signaling.^[90]^[91] As in plants, fungal cell walls necessitate autolytic PCD, bypassing phagocytosis and emphasizing intracellular degradation for tissue remodeling.^[92]

In Microbial and Unicellular Organisms

Programmed cell death (PCD) in microbial and unicellular organisms serves adaptive functions at the population level, such as altruism toward kin, nutrient recycling, and biofilm dynamics, distinct from multicellular developmental roles. In bacteria, PCD enables colony-level benefits under stress, while in unicellular eukaryotes like yeast and protists, it facilitates survival in harsh environments or social aggregation. These processes often involve conserved molecular machinery, though adapted to simpler cellular architectures.^[93] In bacteria, the mazEF toxin-antitoxin (TA) system exemplifies a stress response mechanism implicated in programmed cell death, though its role in actual cell death versus reversible growth arrest remains debated. The mazEF module, encoded on the chromosome of Escherichia coli and other species, consists of the stable toxin MazF, an endoribonuclease that cleaves mRNAs to halt protein synthesis, and the unstable antitoxin MazE, which neutralizes MazF under normal conditions.^[94] Upon stressors like antibiotics or DNA damage, MazE degrades rapidly via the ClpPA protease, freeing MazF to trigger growth arrest that may lead to cell death in some cells, potentially benefiting surviving kin through resource release.^[95] This system promotes persistence and population heterogeneity, as seen in E. coli where mazEF activation generates persister cells resistant to antibiotics.^[96] Bacterial PCD also drives biofilm dispersal through programmed lysis. In Pseudomonas aeruginosa biofilms, a subset of cells undergoes timed death and lysis during development, releasing extracellular DNA (eDNA) that stabilizes the matrix and aids adhesion, while subsequent lysis events facilitate dispersal of viable cells to new niches.^[97] Holin-like proteins, such as CidA/LrgA in Staphylococcus aureus, mediate this lysis by forming pores in the cytoplasmic membrane, analogous to phage-encoded holins that trigger endolysin release for cell wall degradation.^[98] These mechanisms enhance biofilm architecture and antibiotic tolerance, with PCD-linked eDNA contributing significantly to matrix integrity in staphylococcal biofilms.^[99] Among unicellular eukaryotes, slime molds like Dictyostelium discoideum exhibit PCD during social aggregation under starvation. Vegetative amoebae aggregate into a multicellular slug that differentiates into a fruiting body, where approximately 20% of cells become stalk cells that vacuolize, synthesize cellulose walls, and undergo apoptosis-like death to elevate spores for dispersal.^[100] This sacrificial PCD, marked by autophagy and cytoplasmic condensation, contrasts with spore viability; spores remain dormant and resistant, while stalk cells release nutrients that may support kin survival, exemplifying kin selection where related cells benefit from altruists' demise.^[101] In D. discoideum, pre-spore cells can phagocytose undifferentiated or sentinel cells in a form of cannibalism, but stalk cells die without being consumed, underscoring the programmed distinction between viable spores and sacrificial stalk.^[102] In yeast, such as Saccharomyces cerevisiae, acetic acid stress triggers PCD with caspase-like activity. Exposure to acetic acid, mimicking fermentative conditions, induces mitochondrial dysfunction, reactive oxygen species accumulation, and DNA fragmentation, hallmarks of apoptosis.^[103] The metacaspase Yca1p, a functional ortholog of animal caspases, processes substrates to execute death, as yca1 mutants show reduced PCD rates and increased viability under acetic acid.^[104] This PCD clears senescent cells, recycling nutrients for the population and enhancing chronological lifespan in colonies.^[105] Protozoan parasites display PCD linked to kin selection and virulence modulation. In Plasmodium falciparum, the malaria parasite, apoptosis-like PCD occurs in erythrocytic stages under oxidative stress or artemisinin treatment, involving phosphatidylserine externalization and DNA laddering to limit parasite density and prevent host overload, benefiting kin transmission.^[106] Metacaspase orthologs in protists, such as those in Trypanosoma and diatoms, regulate this process; for instance, metacaspases in Leishmania activate under nutrient deprivation, cleaving cellular proteins to promote death and nutrient release for surviving cells.^[107] In phytoplankton like Thalassiosira pseudonana, iron starvation activates metacaspases, inducing PCD that liberates organic matter, sustaining microbial communities.^[108] Overall, these PCD events in pathogens modulate virulence by balancing proliferation and host persistence, as reduced PCD in Toxoplasma gondii mutants increases tissue cysts and chronic infection.^[106] These microbial PCD mechanisms share evolutionary conservation with multicellular apoptosis, such as protease activation and membrane blebbing, suggesting ancient origins in unicellular ancestors.^[14]

Evolutionary Aspects

Origins and Conservation

Programmed cell death (PCD) has deep evolutionary roots in prokaryotes, where toxin-antitoxin (TA) systems serve as precursors to more complex eukaryotic mechanisms. In bacteria such as Escherichia coli, the mazEF TA module exemplifies this, encoding the stable toxin MazF and its antitoxin MazE; under stress conditions like DNA damage or nutrient limitation, MazF activation leads to mRNA cleavage and cessation of protein synthesis, resulting in cell death that promotes population-level persistence and survival of kin.^[109] These systems likely evolved to provide adaptive benefits in clonal populations, such as altruism toward relatives by sacrificing damaged cells to prevent spread of harm or to facilitate biofilm formation and persistence against antibiotics.^[110] The emergence of PCD in eukaryotes is tied to the endosymbiotic event approximately 1.5 billion years ago, when alphaproteobacteria were incorporated as mitochondria, introducing bacterial-like death modules that integrated into host regulatory networks.^[14] Caspases, key executioners of apoptosis in animals, trace their origins to metacaspases found in prokaryotes and unicellular eukaryotes, with phylogenetic analyses indicating divergence at or before the last eukaryotic common ancestor (LECA).^[111] This conservation reflects horizontal gene transfer and endosymbiotic contributions, enabling regulated self-destruction to maintain cellular homeostasis in the nascent eukaryotic lineage.^[112] In metazoans, PCD pathways evolved greater complexity, with core components showing striking homology across bilaterians. The Caenorhabditis elegans genes ced-3, ced-4, and ced-9—encoding a caspase, Apaf-1 homolog, and Bcl-2 homolog, respectively—represent ancestral regulators that predate bilaterian divergence, directly paralleling mammalian apoptotic machinery where Bcl-2 family proteins modulate Apaf-1 and caspase-9 activation.^[113] These ced genes, identified in the 1980s, underscore how nematode PCD pathways inform the evolution of metazoan development, with sequence and functional conservation highlighting their role in sculpting tissues from early animal ancestors.^[114] PCD mechanisms exhibit broad conservation across kingdoms, exemplified by the autophagy-related (Atg) gene core machinery, which is nearly universal in eukaryotes from fungi and plants to animals, facilitating the degradation of damaged organelles and pathogens via lysosome-like vacuoles.^[115] In choanoflagellates, the closest unicellular relatives to metazoans, PCD-like processes involving apoptosis regulators bridge unicellular and multicellular life, supporting colonial formations and hinting at pre-metazoan origins of coordinated cell suicide.^[116] This cross-kingdom persistence of Atg and caspase-like elements emphasizes PCD's role in stress response and nutrient recycling since the LECA. Evolutionarily, PCD confers adaptive advantages through kin selection, where sacrificial death in clonal or viscous populations enhances inclusive fitness by benefiting relatives, as demonstrated in unicellular models where PCD evolves solely via relatedness without direct individual gain.^[117] In transitioning to multicellularity, PCD enabled key innovations like tissue remodeling and suppression of cheater cells, promoting cooperation and preventing uncontrolled proliferation in emerging metazoans.^[14] Such benefits likely drove the fixation of PCD modules in early multicellular lineages, outweighing costs in structured environments. Despite these insights, the fossil record offers limited direct evidence for PCD due to the subtlety of apoptotic morphology, with no preserved cellular suicide events identifiable before the Ediacaran (~635–541 million years ago). Molecular clock analyses, calibrated on metazoan divergences, suggest PCD components originated pre-Ediacaran, potentially during Cryogenian glaciations (>635 million years ago), aligning with the cryptic evolution of early animal precursors.^[118] These estimates highlight gaps in paleontological data, relying instead on genomic phylogenies to infer ancient timelines.^[14]

Mitochondrial Involvement in Apoptosis

The intrinsic pathway of apoptosis is deeply rooted in the endosymbiotic event that gave rise to mitochondria approximately 2 billion years ago, when an ancestral eukaryotic host cell engulfed an alphaproteobacterium, leading to the integration of this prokaryote as a vital organelle.^[119] This symbiosis not only enabled efficient energy production but also provided a mechanism for the host to regulate the endosymbiont's behavior, potentially through controlled release of bacterial components to induce death if the partnership turned parasitic.^[120] Over evolutionary time, these ancient bacterial elements were co-opted into the eukaryotic apoptosis machinery, transforming a prokaryotic survival strategy into a sophisticated program for multicellular regulation.^[111] A prime example of this co-option is cytochrome c, an ancient electron carrier in the bacterial respiratory chain that was repurposed in metazoans to trigger apoptosome formation. In modern apoptosis, cytochrome c is released from the mitochondrial intermembrane space following mitochondrial outer membrane permeabilization (MOMP), where it binds to Apaf-1 and procaspase-9 to assemble the apoptosome and activate downstream caspases. Phylogenetic evidence indicates that this dual role—respiration and death signaling—emerged from the alphaproteobacterial ancestor's machinery, with cytochrome c's heme-binding structure conserved across bacteria and eukaryotes.^[121] Similarly, the MOMP machinery, involving Bcl-2 family proteins like Bax and Bak that form pores in the outer membrane, likely derives from bacterial membrane permeabilizers, such as phage holins or toxin-like structures, as demonstrated by functional substitution experiments where Bax/Bak can replace holins in viral lysis. Bcl-2 homologs or structural analogs in bacteria and plants function as ion channels, modulating membrane permeability in a manner analogous to their role in eukaryotic MOMP.^[122]^[123] Conservation of these components underscores their bacterial origins, with apoptosis-inducing factor (AIF), a flavoprotein released during MOMP to induce caspase-independent DNA fragmentation, showing homology to bacterial toxin-like oxidoreductases involved in redox regulation and cell damage.^[111] Inhibitors of apoptosis proteins (IAPs), which bind and suppress caspases, trace their infectious origins to baculoviruses that captured host IAP genes to evade insect immune responses, later horizontally transferred to eukaryotes.^[124] Phylogenetic analyses further reveal caspase-like peptidases in diverse bacteria, including metacaspase precursors in alphaproteobacteria, suggesting that the proteolytic core of apoptosis evolved from prokaryotic stress-response enzymes predating endosymbiosis.^[125] This integration around 2 billion years ago marked a key event, enabling controlled cell death in early eukaryotes to manage cellular conflicts during the transition to multicellularity.^[126] The evolutionary arms race is evident in viral hijacking of this pathway, where viruses like baculoviruses exploit mitochondrial components—such as IAPs and Bcl-2 homologs—to inhibit host apoptosis and promote replication, highlighting the pathway's ancient vulnerability shaped by prokaryotic-eukaryotic interactions.^[111] Overall, the mitochondrial involvement in apoptosis exemplifies how endosymbiotic bacterial ancestry provided the foundational toolkit for eukaryotic programmed cell death, conserved through phylogenetic pressures.^[127]

Pathological and Clinical Implications

In Cancer and Proliferation Disorders

Programmed cell death (PCD) plays a critical role in suppressing tumorigenesis, but its dysregulation, particularly evasion of apoptosis, is a hallmark of cancer that enables uncontrolled proliferation and survival under stress. Overexpression of anti-apoptotic proteins like Bcl-2, which inhibits mitochondrial outer membrane permeabilization and cytochrome c release, confers resistance to apoptosis in various malignancies, including lymphomas and solid tumors. Similarly, mutations in the TP53 gene, occurring in approximately 50% of human cancers, impair p53's ability to transcriptionally activate pro-apoptotic genes such as BAX and PUMA, thereby allowing cells with genomic instability to evade death and accumulate mutations. This apoptosis resistance not only drives oncogenesis but also underlies chemotherapy resistance, as seen in p53-mutant tumors that fail to undergo treatment-induced cell death despite DNA damage from agents like cisplatin.^[23]^[128]^[129] Autophagy, another form of PCD, exhibits a dual role in cancer progression, acting as a tumor suppressor in early stages and a promoter in advanced disease. Loss of Beclin-1, an essential autophagy initiator, functions as a haploinsufficient tumor suppressor, promoting genomic instability and tumor initiation in models of breast and ovarian cancer, as evidenced by increased tumorigenesis in Beclin-1 heterozygous mice. In contrast, in established tumors, autophagy supports survival under metabolic stress, such as hypoxia in the tumor microenvironment, by recycling cellular components to maintain energy homeostasis and resist anoikis during metastasis. This context-dependent duality highlights autophagy's shift from protective to pro-survival in cancer evolution.^[130]^[131]^[132] Regulated necrosis pathways, including necroptosis, contribute to cancer metastasis by modulating immune responses, with tumor cells often suppressing necroptosis to evade immunosurveillance. Necroptosis, triggered by RIPK3 and MLKL activation, releases damage-associated molecular patterns (DAMPs) that can stimulate anti-tumor immunity, but its inhibition in cancer cells prevents this immunogenic signaling, facilitating immune evasion and metastatic spread, as observed in pancreatic ductal adenocarcinoma models. Oncogenic examples illustrate PCD's complex interplay: the c-Myc oncogene, frequently amplified in cancers, directly induces apoptosis through upregulation of death receptors like DR5 but paradoxically sensitizes cells to extrinsic death signals, potentially limiting tumor progression unless counteracted by survival pathways. In chronic myeloid leukemia, BCR-ABL kinase fusion protects cells from apoptosis by activating PI3K/AKT signaling and upregulating Bcl-2, thereby sustaining leukemic proliferation.^[133]^[134]^[135] Failure of PCD also links to hyperproliferative disorders beyond cancer, such as psoriasis and atherosclerosis, where reduced apoptotic clearance exacerbates tissue pathology. In psoriasis, keratinocytes exhibit resistance to apoptosis due to dysregulated Bcl-2 family proteins and impaired Fas-mediated signaling, leading to epidermal hyperplasia and chronic plaque formation. Similarly, in atherosclerosis, insufficient apoptosis of vascular smooth muscle cells and macrophages in plaques contributes to their buildup and instability, promoting occlusive disease through unchecked cellular accumulation. The DNA damage response (DDR) integrates PCD to prevent oncogenesis, as unrepaired lesions activate p53-dependent apoptosis via ATM/ATR kinases, eliminating potentially malignant cells before clonal expansion; defects in this pathway, such as in BRCA-mutant cancers, allow survival of damaged cells and tumor initiation.^[136]^[137]^[138]

In Neurodegenerative and Aging Processes

The neurotrophic theory posits that the survival of neurons is determined by limited availability of trophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which are produced by target tissues to support a precise number of innervating neurons.^[139] In development, competition for these factors results in excess programmed cell death (PCD), eliminating more than half (up to 70% in some populations) of neurons to match target size, a process mediated by apoptosis through pathways like PI3K-Akt for survival and BH3-only proteins (e.g., Bim) for death upon factor withdrawal.^[139] In adulthood, imbalances in these factors contribute to neurodegeneration, where insufficient neurotrophin signaling fails to prevent PCD, leading to neuronal loss in conditions like Alzheimer's and Parkinson's diseases.^[140] In Alzheimer's disease, amyloid-β (Aβ) peptides induce neuronal apoptosis primarily through the intrinsic pathway, involving limited activation of caspases-3 and -9 via cytochrome c release and Apaf-1 apoptosome formation, without significant engagement of the extrinsic pathway.^[141] Hyperphosphorylated tau forming neurofibrillary tangles exacerbates this by stimulating necroptosis, a regulated inflammatory form of PCD, through upregulation of necroptotic components like RIPK1 and MLKL in affected neurons.^[142] These mechanisms result in synaptic loss and progressive neuronal death, hallmarks of the disease.^[143] In Parkinson's disease, α-synuclein aggregates impair mitochondrial function by localizing to mitochondrial membranes, reducing oxygen consumption and ATP production while increasing reactive oxygen species (ROS).^[144] This leads to mitophagy failure, where elevated α-synuclein inhibits the flux of damaged mitochondria clearance, causing their accumulation and exacerbating proteotoxic stress.^[145] Consequently, neurons undergo ferroptosis, driven by iron dysregulation, lipid peroxidation, and glutathione peroxidase 4 (GPX4) depletion, contributing to dopaminergic cell loss in the substantia nigra.^[146] During aging, cumulative DNA damage in neurons, arising from oxidative stress and replication errors, activates PCD pathways such as p53-mediated apoptosis, overwhelming repair mechanisms and leading to cellular senescence or death.^[147] Telomere shortening further sensitizes neurons by inducing a persistent DNA damage response, promoting pro-inflammatory senescence-associated secretory phenotype (SASP) factors that amplify neuronal vulnerability to PCD.^[148] These processes underlie age-related neuronal attrition, particularly in post-mitotic cells like those in the hippocampus and cortex.^[147] Neurons in the peripheral nervous system (PNS) exhibit greater tolerance to PCD compared to those in the central nervous system (CNS), owing to enhanced regenerative capacity that allows axonal regrowth without inevitable cell body loss following injury or stress.^[149] In contrast, CNS neurons are more vulnerable, with limited regeneration and heightened susceptibility to apoptosis via BCL-2 family dysregulation, resulting in irreversible loss after axonal degeneration or neurodegenerative insults.^[149] Invertebrate models like Caenorhabditis elegans provide insights into aging-related PCD, where mitochondrial intrinsic apoptosis pathways, modulated by proteins such as CISD-1, regulate proteostasis and lifespan, with deficiencies accelerating neurodegeneration akin to human tauopathies and α-synucleinopathies.^[150] These models highlight conserved mechanisms, including autophagy-apoptosis coupling, that influence neuronal survival during aging.^[150]

Therapeutic Interventions

Therapeutic interventions in programmed cell death (PCD) aim to modulate apoptotic, autophagic, and other regulated death pathways to treat diseases such as cancer and neurodegeneration. Pro-apoptotic agents, particularly BH3 mimetics, target anti-apoptotic proteins like Bcl-2 to restore cell death in resistant tumors. Venetoclax, a selective Bcl-2 inhibitor, was approved by the FDA in 2016 for relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletion and has since been expanded to additional indications including relapsed/refractory CLL or small lymphocytic lymphoma (SLL) regardless of 17p status (2018), frontline CLL in combination with obinutuzumab (2019), and newly diagnosed acute myeloid leukemia (AML) with azacitidine, decitabine, or low-dose cytarabine (2020), demonstrating high response rates in clinical trials by mimicking BH3-only proteins to promote mitochondrial outer membrane permeabilization; a combination with acalabrutinib for previously untreated CLL was submitted for approval in July 2025.^[151]^[152] TRAIL agonists, which activate death receptors to induce extrinsic apoptosis, have shown promise in preclinical models and early-phase trials for various solid tumors, though challenges with systemic toxicity have limited monotherapy efficacy; combinations with chemotherapy enhance tumor-specific killing while sparing normal cells.^[153] For neuroprotection, anti-PCD strategies inhibit excessive cell death in acute injuries like stroke. Caspase inhibitors, such as broad-spectrum agents like Z-VAD-fmk, have demonstrated neuroprotective effects in preclinical stroke models by blocking apoptotic cascades, with several reaching phase II clinical trials, though outcomes varied due to delivery timing and blood-brain barrier penetration issues.^[154] Necroptosis blockers targeting RIPK1, including GSK'872, reduce inflammation and neuronal loss in models of neurodegeneration and ischemia by preventing MLKL phosphorylation and membrane rupture, offering potential for conditions like Parkinson's disease where necroptosis contributes to dopaminergic neuron death.^[155] Autophagy modulators exploit PCD's dual role in survival and death. In neurodegeneration, rapamycin analogs like everolimus activate autophagy via mTOR inhibition to clear protein aggregates, showing lifespan extension and reduced pathology in models of Alzheimer's and Parkinson's, with ongoing trials evaluating safety in human cognitive decline.^[156] Conversely, in cancer, autophagy inhibition sensitizes tumors to therapy; chloroquine, a lysosomal acidification blocker, enhances chemotherapy efficacy in colorectal and breast cancers by preventing autophagosome-lysosome fusion, as evidenced in phase I/II trials where it improved response rates without severe toxicity.^[157] Gene therapies provide precise PCD modulation. CRISPR-Cas9 editing of p53 restores wild-type function in mutant tumors, inducing apoptosis in preclinical cancer models, with early trials exploring AAV-delivered systems for hematologic malignancies.^[158] For autophagy, CRISPR knockout of Atg genes like Atg5 or Atg7 impairs flux in cancer cells, synergizing with ferroptosis inducers, while therapeutic activation via editing has potential in neurodegeneration.^[159] Viral vectors, such as AAV, deliver neurotrophins like BDNF to inhibit PCD pathways, providing neuroprotection in Parkinson's models by promoting neuronal survival and reducing caspase activation.^[160] Challenges in PCD therapies include extensive pathway crosstalk, where inhibiting one mechanism (e.g., apoptosis) may activate alternatives like necroptosis, complicating outcomes in heterogeneous diseases.^[161] Off-target effects, such as unintended immune activation or toxicity to healthy tissues, further hinder translation, as seen in early TRAIL agonist trials.^[162] Whole-organism models like C. elegans reveal insights into PCD's role in aging, where modulating ced-3/ced-4 apoptotic genes extends lifespan but highlights risks of systemic dysregulation.^[163] Recent advances post-2020 focus on ferroptosis inducers for therapy-resistant cancers. Derivatives of erastin, such as imidazole ketone erastin (IKE), inhibit GPX4 and system xc-, selectively killing tumor cells with high iron dependency, showing efficacy in pancreatic and lung cancer xenografts with minimal normal cell impact.^[164] These agents are entering combination trials, leveraging ferroptosis' independence from canonical apoptosis to overcome resistance. As of 2024, novel MCL1 inhibitors like BRD-810 have demonstrated rapid apoptosis induction in preclinical cancer models, offering potential to overcome Bcl-2 inhibitor resistance.^[165]^[166]

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Cell Death by Entosis: Triggers, Molecular Mechanisms and Clinical ...
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Paraptosis is a distinct form of regulated cell death characterized by cytoplasmic vacuolation and dilatation of cellular organelles like the mitochondria and ...
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Metacaspases, a family of cysteine proteases, play critical roles in programmed cell death during plant development and defense responses.
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Metacaspases in Leishmania instead of caspase and death receptors in mammals play the same role in the PCD pathways.
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Choanoflagellate phylogeny: evolution of Metazoan multicellularity
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The successes and failures of the most recent clinical trials using TRAIL agonists are discussed and we provide a perspective for improving its clinical ...
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