Apoptosis Signaling Pathways and Regulated Cell Death Research

Apoptosis is a form of programmed cell death regulated by genes and protein networks. It mainly functions to eliminate senescent, damaged, abnormally proliferating, or functionally imbalanced cells. Typical apoptosis is characterized by cell shrinkage, chromatin condensation, DNA fragmentation, caspase cascade activation, and apoptotic body formation. Abnormal apoptosis is closely associated with tumors, autoimmune diseases, ischemic injury, AIDS, neurodegenerative diseases, and other pathological conditions.

Keywords: apoptosis; extrinsic apoptotic pathway; mitochondrial apoptotic pathway; caspase; Bcl-2 family; IAP; p53; ferroptosis; necroptosis; pyroptosis

1 Basic Logic of Apoptosis Research

1.1 Biological Significance of Apoptosis

Apoptosis is not merely a cell death phenomenon, but an important regulatory mechanism for maintaining tissue homeostasis, developmental morphogenesis, and immune balance. Under physiological conditions, apoptosis eliminates aged cells, cells with severe DNA damage, abnormally activated immune cells, and potential tumor cells. Under pathological conditions, either excessive or insufficient apoptosis may lead to disease.

(1) Insufficient apoptosis

Insufficient apoptosis allows damaged cells, abnormally proliferating cells, or autoreactive immune cells to survive persistently, and is commonly associated with tumorigenesis, therapeutic tolerance, and autoimmune lymphoproliferation.

(2) Excessive apoptosis

Excessive apoptosis can cause massive loss of tissue cells and is commonly observed in ischemia-reperfusion injury, neurodegenerative diseases, virus infection-related cell depletion, and drug-induced toxic injury.

(3) Apoptosis and tissue homeostasis

Apoptotic cells are usually engulfed and cleared by macrophages or neighboring cells. If clearance is delayed, late-stage apoptotic cells may undergo secondary necrosis, release cellular contents, and induce inflammatory responses.

1.2 Distinguishing Apoptosis from Other Forms of Regulated Cell Death

Cell death research should not classify all death phenomena as apoptosis. Ferroptosis, necroptosis, pyroptosis, cuproptosis, paraptosis, and other forms of regulated cell death differ in triggering mechanisms, molecular markers, and detection indicators.

Table 1 Comparison of Apoptosis and Other Forms of Regulated Cell Death

Cell Death Form	Core Mechanism	Typical Molecules	Common Interpretation Indicators
Apoptosis	caspase cascade, mitochondrial outer membrane permeabilization, DNA fragmentation	caspase-8, caspase-9, caspase-3, Bax, Bcl-2, PARP	Annexin V, cleaved caspase-3, cleaved PARP, TUNEL
Necroptosis	RIPK1/RIPK3/MLKL-mediated membrane rupture-associated death	RIPK1, RIPK3, p-MLKL	p-MLKL, membrane integrity disruption, Nec-1 sensitivity
Pyroptosis	Inflammatory lytic death mediated by inflammasomes and Gasdermin	NLRP3, caspase-1, GSDMD, IL-1β	GSDMD cleavage, IL-1β release, LDH release
Ferroptosis	Iron-dependent accumulation of lipid peroxidation	GPX4, SLC7A11, ACSL4, TFRC	Lipid ROS, MDA, 4-HNE, iron ions, GPX4 reduction
Cuproptosis	Copper-induced aggregation of mitochondrial lipoylated proteins and proteotoxic stress	FDX1, DLAT, LIAS	Copper-dependent cell death and abnormal mitochondrial metabolism
Paraptosis	Non-caspase-dependent cell death often accompanied by ER/mitochondrial swelling	MAPK, IGF1R-related signaling	Cytoplasmic vacuolization, caspase insensitivity, ER/mitochondrial dilation

 

Figure 1 Simplified schematic diagram of apoptosis and necroptosis signaling pathways

2 Extrinsic Apoptotic Pathway

2.1 Death Receptor-Mediated Signal Initiation

(1) Mechanistic core

The extrinsic apoptotic pathway is mediated by cell membrane death receptors (DRs). After death ligands such as FasL, TNF-α, and TRAIL bind to their corresponding receptors, intracellular death domains of the receptors are clustered, and the adaptor protein FADD and initiator caspase-8 are recruited to form the death-inducing signaling complex (DISC).

(2) Key molecules

Typical molecules include Fas/CD95, TNF receptor, TRAIL receptor, FADD, caspase-8, and c-FLIP. After DISC formation, caspase-8 is activated and further initiates the effector caspase cascade.

(3) Result interpretation

If FasL, TNF-α, or TRAIL treatment induces caspase-8 cleavage, caspase-3 activation, and PARP cleavage, activation of the extrinsic apoptotic pathway is usually supported. If death receptors are upregulated but caspase-8 is not activated, insufficient DISC assembly, c-FLIP inhibition, or switching to alternative pathways such as necroptosis should be considered.

2.2 Caspase-8 and the Effector Caspase Cascade

(1) Mechanistic core

Caspase-8 is an important initiator caspase in the extrinsic apoptotic pathway. After activation, it can directly cleave and activate caspase-3, caspase-6, and caspase-7. It can also cleave Bid into tBid, amplifying death receptor signals into the mitochondrial pathway.

(2) Experimental indicators

Common indicators include cleaved caspase-8, cleaved caspase-3, cleaved caspase-7, cleaved PARP, Annexin V positivity, and DNA fragmentation.

(3) Result interpretation

Caspase-3 cleavage is a commonly used apoptosis marker, but it cannot distinguish the extrinsic pathway from the intrinsic pathway by itself. If caspase-8 is activated before caspase-9 and blockade of death receptors reduces apoptosis, dominance of the extrinsic pathway is better supported.

2.3 Dual Effects of TNF Signaling

(1) Mechanistic core

Binding of TNF-α to TNF receptors does not necessarily induce apoptosis. TNFR signaling can form different complexes. A membrane-proximal complex can activate NF-κB and pro-survival signaling. When intracellular conditions change, a death complex containing FADD and caspase-8 can form and induce apoptosis.

(2) Experimental indicators

TNF receptor, FADD, caspase-8, NF-κB activation, IκBα degradation, cell survival, and inflammatory factor expression should be detected simultaneously.

(3) Result interpretation

Increased TNF-α does not directly indicate that cells are undergoing apoptosis. If TNF signaling mainly activates NF-κB and induces survival factor expression, cells may show inflammatory activation rather than apoptosis. Only when caspase-8 and downstream effector caspases are activated is TNF-related apoptosis supported.

Table 2 Key Nodes in the Extrinsic Apoptotic Pathway

Signaling Node	Representative Molecules	Main Role	Interpretation Focus
Death ligands	FasL, TNF-α, TRAIL	Initiate death receptor signaling	Increased ligand level does not equal apoptosis; receptors and caspases should be evaluated together
Death receptors	Fas, TNFR, TRAILR	Transmit membrane receptor death signals	DISC formation and downstream caspase activation should be observed
Adaptor protein	FADD	Connects receptors with caspase-8	FADD loss or abnormality can weaken extrinsic apoptosis
Initiator caspase	caspase-8	Activates effector caspases or cleaves Bid	Can connect extrinsic and mitochondrial pathways
Effector caspases	caspase-3, caspase-6, caspase-7	Execute apoptotic morphology and substrate cleavage	Cleaved caspase-3 is commonly used as a core readout

3 Intrinsic Mitochondrial Apoptotic Pathway

3.1 Bcl-2 Family Regulation of Mitochondrial Outer Membrane Permeabilization

(1) Mechanistic core

The intrinsic apoptotic pathway is mainly determined by mitochondrial outer membrane permeabilization (MOMP). Bcl-2 family proteins are the core regulators of this process. Pro-apoptotic members include Bid, Bim, Bax, and Bak, whereas anti-apoptotic members include Bcl-2, Bcl-xL, and Mcl-1.

(2) Key mechanism

After activation, Bax and Bak can form pores in the mitochondrial outer membrane and promote cytochrome c release. Anti-apoptotic Bcl-2 family proteins can inhibit Bax/Bak activation, thereby preventing initiation of the mitochondrial pathway.

(3) Result interpretation

An increased Bax/Bcl-2 ratio often suggests that cells are more prone to apoptosis, but it cannot replace functional validation. More reliable evidence includes loss of mitochondrial membrane potential, cytochrome c release, caspase-9 activation, and caspase-3/PARP cleavage.

3.2 Cytochrome c and Apoptosome Formation

(1) Mechanistic core

After cytochrome c is released from mitochondria, it can form the apoptosome with Apaf-1 and procaspase-9, further activating caspase-9. Caspase-9 then activates caspase-3 and caspase-7, completing the execution phase of apoptosis.

(2) Experimental indicators

Mitochondrial membrane potential, cytosolic cytochrome c, Apaf-1, cleaved caspase-9, cleaved caspase-3, and cleaved PARP are commonly detected.

(3) Result interpretation

A decrease in mitochondrial membrane potential does not always represent apoptosis; it may also occur in necrosis, ferroptosis, or metabolic failure. Therefore, mitochondrial indicators should be interpreted together with caspase activation, Annexin V, TUNEL, and related results.

3.3 Bid Links the Extrinsic and Intrinsic Pathways

(1) Mechanistic core

After activation of caspase-8 in the extrinsic pathway, Bid can be cleaved into tBid. tBid translocates to mitochondria and promotes Bax/Bak activation, thereby amplifying death receptor signaling into mitochondrial apoptotic signaling.

(2) Experimental indicators

tBid, mitochondrial translocation of Bax, cytochrome c release, and simultaneous activation of caspase-8 and caspase-9 are commonly detected.

(3) Result interpretation

If death receptor stimulation simultaneously triggers caspase-8 activation and mitochondrial injury, the extrinsic pathway may amplify apoptosis through Bid. If caspase-8 inhibition reduces mitochondrial injury, this connection is further supported.

4 Apoptosis Execution Phase and Detection Interpretation

4.1 Caspase-3, Caspase-6, and Caspase-7

(1) Mechanistic core

Caspase-3, caspase-6, and caspase-7 are the major proteases in the execution phase of apoptosis. They cleave structural proteins, repair proteins, and regulatory proteins, causing cell shrinkage, DNA fragmentation, cytoskeletal remodeling, and apoptotic body formation.

(2) Experimental indicators

Cleaved caspase-3, cleaved caspase-7, cleaved PARP, DNA ladder, TUNEL, Annexin V, and nuclear morphology are commonly detected.

(3) Result interpretation

Annexin V positivity can indicate phosphatidylserine externalization, but early apoptosis, late apoptosis, and some non-apoptotic membrane changes can all affect results. More reliable apoptosis interpretation should combine caspase cleavage, PARP cleavage, and cellular morphology.

4.2 PARP Cleavage and Interruption of DNA Repair

(1) Mechanistic core

PARP participates in DNA damage repair. During apoptosis, caspase-3 can cleave PARP, stopping energy-consuming DNA repair processes and promoting irreversible progression of apoptosis.

(2) Experimental indicators

Cleaved PARP, total PARP, γH2AX, TUNEL, and cell viability are commonly detected.

(3) Result interpretation

Cleaved PARP is a common marker of apoptosis, but PARP also participates in DNA damage repair and energy depletion associated with necrotic cell death. If only PARP changes are observed, caspase-3 and Annexin V/TUNEL should be combined for interpretation.

4.3 Regulation by IAPs and Survivin

(1) Mechanistic core

IAPs, or inhibitors of apoptosis proteins, can inhibit caspase activity and restrict apoptosis execution. Survivin is a member of the IAP family and is often highly expressed in tumor cells. It is associated with cell division, anti-apoptosis, and therapeutic tolerance.

(2) Experimental indicators

XIAP, cIAP1/2, Survivin, cleaved caspase-3, cell cycle distribution, drug sensitivity, and apoptotic proportion are commonly detected.

(3) Result interpretation

Increased IAP or Survivin usually indicates stronger anti-apoptotic capacity, but whether it truly causes therapeutic tolerance requires validation through IAP inhibition, restored caspase activation, and changes in drug sensitivity.

Table 3 Apoptosis Detection Indicators and Interpretation Points

Detection Indicator	Main Significance	Notes
Annexin V	Phosphatidylserine externalization; commonly used for early apoptosis detection	PI or 7-AAD should be combined to distinguish early apoptosis from late-stage death
cleaved caspase-3	Effector caspase activation	A key apoptosis indicator, but upstream pathway source should be interpreted together
cleaved caspase-8	Initiation of extrinsic pathway	Can connect to the mitochondrial pathway through Bid
cleaved caspase-9	Initiation of intrinsic mitochondrial pathway	Should be combined with mitochondrial membrane potential and cytochrome c release
cleaved PARP	caspase-mediated PARP cleavage	Does not independently represent the complete apoptotic mechanism
TUNEL	DNA break labeling	Severe necrosis or other DNA breaks may also yield positive signals
Decreased mitochondrial membrane potential	Mitochondrial functional impairment	Non-apoptotic mitochondrial injury should be excluded

5 p53, c-Myc, and Apoptosis Regulation

5.1 p53-Mediated Damage Response

(1) Mechanistic core

p53 is a key fate-regulating factor after DNA damage, replication stress, and cellular stress. Under mild to moderate damage, p53 can induce p21 expression and cause cell cycle arrest. When damage is severe or repair fails, p53 can induce expression of pro-apoptotic genes such as Bax, PUMA, and NOXA, promoting mitochondrial apoptosis.

(2) Regulatory node

MDM2 promotes p53 ubiquitination and degradation and is an important negative regulator of the p53 pathway. Abnormalities in the MDM2/p53 axis can allow cells to evade damage-induced apoptosis.

(3) Result interpretation

Increased p53 does not necessarily equal apoptosis. p53-mediated apoptosis is supported only when p53 activation is accompanied by upregulation of pro-apoptotic target genes, mitochondrial injury, and caspase activation. If p21 is mainly induced, the outcome may be dominated by cell cycle arrest or senescence.

5.2 c-Myc and Apoptosis Sensitivity

(1) Mechanistic core

c-Myc promotes cell growth and proliferation, but under nutrient deprivation, DNA damage, or insufficient survival signaling, it can also increase cellular sensitivity to apoptosis. Its function is strongly context-dependent.

(2) Experimental indicators

c-Myc, cell proliferation, p53, Bim, Bax, caspase activation, and cell death proportion are commonly detected.

(3) Result interpretation

Increased c-Myc may represent proliferative drive, but it may also make cells more prone to apoptosis under stress. Interpretation of c-Myc results must consider survival signaling, nutritional status, and DNA damage background.

6 Apoptosis and Disease Mechanisms

6.1 Tumors

(1) Mechanistic characteristics

Tumor cells often evade apoptosis by upregulating Bcl-2, Bcl-xL, Mcl-1, IAPs, and Survivin, or by p53 inactivation, weakened death receptor signaling, or abnormal caspase expression. Apoptosis escape can promote tumor progression and therapeutic tolerance.

(2) Research indicators

Bcl-2 family proteins, p53, MDM2, IAPs, caspase cleavage, PARP cleavage, colony formation, drug IC50, and resistant cell models are commonly detected.

(3) Result interpretation

A decrease in tumor cell viability after drug treatment does not equal apoptosis induction. To prove that apoptosis participates in drug efficacy, caspase-dependent evidence should be observed, and cell death should be partially reversed by caspase inhibitors.

6.2 Autoimmunity and Lymphoproliferation

(1) Mechanistic characteristics

Immune cells need to eliminate abnormally activated or autoreactive clones through apoptosis. Abnormal Fas/FasL signaling can impair lymphocyte clearance and promote autoimmunity and lymphoproliferation.

(2) Research indicators

Fas, FasL, caspase-8, T/B cell apoptosis proportion, inflammatory factors, and abnormal lymphocyte expansion are commonly detected.

(3) Result interpretation

Increased lymphocyte number does not necessarily result from enhanced proliferation; it may also result from insufficient apoptotic clearance. Proliferation and apoptosis indicators should be detected simultaneously.

6.3 AIDS and Infection-Related Cell Death

(1) Mechanistic characteristics

Viral infection can induce immune cell loss through multiple mechanisms, including immune activation, death receptor signaling, mitochondrial injury, and inflammatory cell death. In AIDS, CD4⁺ T cell reduction is associated with multiple cell death mechanisms.

(2) Research indicators

T cell apoptosis, Fas/FasL, caspase activation, mitochondrial membrane potential, inflammatory factors, and viral replication levels are commonly detected.

(3) Result interpretation

Cell death in infection models is not necessarily all apoptosis. Apoptosis, pyroptosis, necroptosis, and direct viral lytic effects should be distinguished.

6.4 Ischemic Injury and Neurodegenerative Diseases

(1) Mechanistic characteristics

Ischemia, oxidative stress, Ca²⁺ overload, mitochondrial dysfunction, and protein aggregation can all induce apoptosis in neurons or tissue cells. In neurodegenerative diseases, apoptosis is often intertwined with oxidative stress, ferroptosis, inflammation, and protein homeostasis abnormalities.

(2) Research indicators

Mitochondrial membrane potential, Bax/Bcl-2, cleaved caspase-3, TUNEL, ROS, ferroptosis indicators, and neuronal survival are commonly detected.

(3) Result interpretation

In nervous system injury, TUNEL positivity or increased caspase does not explain all cell death. If lipid peroxidation, GPX4 reduction, and iron accumulation are also present, ferroptosis should be considered as a co-participating mechanism.

7 Apoptosis-Targeted Intervention Strategies

7.1 Therapeutic Strategies That Promote Apoptosis

(1) Bcl-2 inhibition

Inhibition of Bcl-2, Bcl-xL, or Mcl-1 can release anti-apoptotic protection and make tumor cells more prone to mitochondrial apoptosis. This strategy is commonly used in tumors highly dependent on anti-apoptotic Bcl-2 family proteins.

(2) IAP inhibition

IAP inhibitors can release caspases from inhibition and increase cellular sensitivity to death receptor signaling or chemotherapeutic drugs.

(3) MDM2/p53 regulation

In a p53 wild-type background, MDM2 inhibition can stabilize p53 and enhance damage response and apoptotic tendency. If p53 is mutated or lost, this strategy usually has limited efficacy.

(4) Death receptor activation

Strategies targeting Fas, TRAIL receptors, or TNF-related pathways can directly initiate extrinsic apoptosis, but inflammatory responses, tissue toxicity, and receptor expression differences should be considered.

7.2 Protective Strategies That Inhibit Apoptosis

(1) Caspase inhibition

In ischemia-reperfusion, neural injury, and acute toxic injury, caspase inhibition may reduce cell loss. However, long-term apoptosis inhibition may increase the risk of abnormal cell survival.

(2) Akt/PKB pathway activation

Akt signaling can promote cell survival and inhibit some pro-apoptotic factors. This strategy may be beneficial for tissue protection, but in tumor contexts it may promote therapeutic tolerance.

(3) PARP regulation

PARP participates in DNA repair and cell death. Moderate PARP inhibition may reduce energy depletion or produce synthetic lethality, but its role differs across disease contexts.

7.3 Combined Regulation with Other Cell Death Modes

(1) Apoptosis and ferroptosis

When some tumor cells are insensitive to apoptosis, inducing ferroptosis may serve as an alternative strategy. Ferroptosis research should focus on GPX4, lipid ROS, GSH, TFRC, and iron metabolism.

(2) Apoptosis and necroptosis

When caspase-8 is inhibited, cells may switch to RIPK1/RIPK3/MLKL-mediated necroptosis. In research on death receptor pathways, both caspase-dependent and RIPK-dependent routes should be considered.

(3) Apoptosis and pyroptosis

Inflammasome activation can induce pyroptosis and release inflammatory mediators such as IL-1β and IL-18. If cell death is accompanied by GSDMD cleavage and inflammatory factor release, it should not be simply classified as apoptosis.

Table 4 Apoptosis Intervention Strategies and Applicable Scenarios

Intervention Direction	Representative Targets	Expected Result	Applicable Scenario
Promoting extrinsic apoptosis	Fas, TNFR, TRAILR, caspase-8	Initiation of death receptor signaling	Tumor cell death and immune clearance research
Promoting mitochondrial apoptosis	Bcl-2, Bcl-xL, Mcl-1, Bax/Bak	Induction of MOMP and caspase-9 activation	Tumor therapy and chemosensitivity research
Releasing caspase inhibition	IAP, Survivin	Enhanced effector caspase activity	Apoptosis tolerance and tumor resistance research
Stabilizing p53	MDM2/p53	Enhanced damage-induced apoptosis	p53 wild-type tumor research
Inhibiting excessive apoptosis	caspase, PARP, mitochondrial injury	Protection of cell survival	Ischemia, neurodegenerative diseases, and toxic injury research
Inducing non-apoptotic death	GPX4, RIPK, GSDMD, cuproptosis-related molecules	Bypassing apoptosis tolerance	Apoptosis-resistant tumors or inflammatory cell death research

Table 5 Representative Products Related to Apoptosis and Regulated Cell Death Research

Research Module	Representative Product	CAS No.	Mechanism or Detection Positioning	Applicable Research
Positive control for apoptosis induction	Staurosporine	62996-74-1	Broad-spectrum kinase inhibitor commonly used to induce caspase-dependent apoptosis	Apoptosis model establishment and detection of cleaved caspase-3 and PARP cleavage
DNA damage-induced apoptosis	Etoposide	33419-42-0	Topoisomerase II inhibitor that induces DNA double-strand breaks	DNA damage response, p53 pathway, and apoptosis induction research
DNA damage-induced apoptosis	Camptothecin	7689-03-4	Topoisomerase I inhibitor that induces replication-associated DNA damage	γH2AX, caspase activation, and tumor cell efficacy research
Chemotherapy-induced apoptosis	Doxorubicin hydrochloride	25316-40-9	DNA intercalation and topoisomerase II-related damage	Chemotherapy-induced apoptosis, p53 response, and resistance mechanism research
Caspase cascade inhibition	Z-VAD-FMK	187389-52-2	Pan-caspase inhibitor	Verifying whether cell death depends on the caspase cascade
Caspase-3 pathway inhibition	Ac-DEVD-CHO	169332-60-9	caspase-3-related inhibitor	Effector caspase functional validation, PARP cleavage, and apoptosis execution phase research
Bcl-2 family inhibition	ABT-737	852808-04-9	Bcl-2/Bcl-xL/Bcl-w inhibitor	Mitochondrial apoptosis, Bax/Bak dependence, and tumor cell apoptosis sensitivity research
Bcl-2 targeting research	Venetoclax	1257044-40-8	Selective Bcl-2 inhibitor	Bcl-2-dependent tumors, MOMP, and mitochondrial apoptosis research
Bcl-2/Bcl-xL inhibition	Navitoclax	923564-51-6	Bcl-2/Bcl-xL inhibitor	Anti-apoptotic escape, BH3 mimetics, and combination efficacy research
Mcl-1 targeting research	S63845	1799633-27-4	Mcl-1 inhibitor	Mcl-1-dependent survival, mitochondrial apoptosis, and resistance mechanism research
IAP inhibition research	Birinapant	1260251-31-7	Smac mimetic/IAP antagonist	IAP-mediated apoptosis escape, restored caspase activation, and tumor resistance research
IAP inhibition research	BV6	1001600-56-1	IAP inhibitor	TNF-related cell death and switching between apoptosis and necroptosis
p53 stabilization research	Nutlin-3a	675576-98-4	MDM2-p53 interaction inhibitor	p53 wild-type tumors, p21/PUMA/NOXA expression, and apoptosis induction research
PARP-related cell death research	Olaparib	763113-22-0	PARP inhibitor	DNA repair inhibition, synthetic lethality, and PARP-related cell death research
Necroptosis inhibition	Necrostatin-1	4311-88-0	RIPK1 inhibitor	TNF-related necroptosis and validation of RIPK1-dependent death
MLKL-related necroptosis	Necrosulfonamide	1360614-48-7	MLKL inhibitor	p-MLKL-related membrane rupture-associated death and necroptosis validation
Ferroptosis induction	Erastin	571203-78-6	Inhibits system xc⁻ and induces GSH depletion and lipid peroxidation	Ferroptosis models, SLC7A11/GPX4 axis, and apoptosis-resistant cell death research
Ferroptosis induction	RSL3	1219810-16-8	GPX4 inhibitor	GPX4-dependent antioxidant defense, lipid ROS, and ferroptosis mechanism research
Ferroptosis inhibition	Ferrostatin-1	347174-05-4	Lipid peroxidation inhibitor	Verifying whether cell death has ferroptotic features
Ferroptosis/iron homeostasis research	Deferoxamine mesylate	138-14-7	Iron chelator	Iron-dependent death, iron overload, and oxidative injury research
Pyroptosis/NLRP3 research	MCC950	210826-40-7	NLRP3 inflammasome inhibitor	Pyroptosis, IL-1β release, and inflammasome-related cell death research
Caspase-1-related pyroptosis	Ac-YVAD-CMK	178603-78-6	caspase-1 inhibitor	GSDMD cleavage, IL-1β maturation, and inflammatory cell death research
Cuproptosis research	Elesclomol	488832-69-5	Copper ionophore that promotes copper-dependent cell death	Cuproptosis, mitochondrial metabolism, and tumor cell death research
Photodynamic cell death induction	5-Aminolevulinic acid hydrochloride	5451-09-2	Photosensitizer precursor that promotes PDT-related ROS generation	Photodynamic therapy, ROS-mediated apoptosis, and tumor cell killing research

Table 6 Product Lines Related to Apoptosis and Regulated Cell Death and Application Directions

Research Direction	Product Line	Covered Object/Target	Applicable Research Direction
Overview of apoptosis research	Apoptosis	Apoptosis-related proteins, detection reagents, and regulatory molecules	Extrinsic/intrinsic apoptosis, caspase cascade, drug-induced cell death, and disease mechanism research
Death receptor signaling research	TNF Receptor	TNFR and related death receptor signaling	TNF-mediated apoptosis, inflammation, survival signaling, and switching to necroptosis
Mitochondrial apoptosis research	Bcl-2 Family	Bcl-2, Bcl-xL, Mcl-1, Bax, Bak, and others	Mitochondrial outer membrane permeabilization, anti-apoptotic escape, tumor resistance, and BH3 mimetic research
Caspase cascade research	Caspase	Caspase family and related cysteine proteases	Initiator caspases, effector caspases, PARP cleavage, and apoptosis execution phase research
p53 regulation research	MDM-2/p53	MDM2, p53, and their regulatory network	DNA damage response, p53 stability, p21/PUMA/NOXA expression, and tumor apoptosis research
Pro-apoptotic kinase research	ASK1	Apoptosis signal-regulating kinase 1	Oxidative stress, JNK/p38 pathway, stress-induced apoptosis, and inflammatory injury research
Pro-apoptotic kinase research	DAPK	Death-associated protein kinase	Cell death, calcium/calmodulin-related signaling, tumor suppression, and neural injury research
Anti-apoptotic mechanism research	IAP	XIAP, cIAP, and Survivin-related inhibitory proteins	caspase inhibition, apoptosis escape, tumor resistance, and IAP inhibitor research
Anti-apoptotic mechanism research	Survivin	Survivin/BIRC5	Mitosis, anti-apoptosis, tumor proliferation, therapeutic tolerance, and prognostic marker research
Cell proliferation and apoptosis balance research	c-Myc	c-Myc and its downstream regulatory network	Proliferative drive, stress-induced apoptosis sensitivity, tumor progression, and metabolic reprogramming research
Protein folding and stress research	FKBP	FK506-binding protein family	Protein folding, mTOR-related signaling, stress tolerance, and cell death regulation
Photodynamic death induction research	Photosensitizer	Photosensitizers and ROS generation-related tools	Photodynamic therapy, ROS-mediated apoptosis, tumor cell killing, and mitochondrial injury research
Thymidylate synthesis research	Thymidylate Synthase	TS/TYMS and nucleotide synthesis-related targets	DNA synthesis inhibition, S phase stress, antimetabolic drugs, and apoptosis induction research
Necroptosis research	Necroptosis	RIPK1/RIPK3/MLKL-related molecules	caspase-independent death, inflammatory membrane rupture, and cell death mode switching
RIPK signaling research	RIP kinase	RIPK1, RIPK3, and related kinases	TNF signaling, necroptosis, inflammatory injury, and crosstalk among cell death pathways
Pyroptosis research	Pyroptosis	Inflammasomes, caspase-1, GSDMD, and related molecules	Inflammatory cell death, IL-1β release, infectious inflammation, and tumor immunity research
Ferroptosis research	Ferroptosis	GPX4, SLC7A11, ACSL4, and iron metabolism-related targets	Lipid peroxidation, iron-dependent death, neurotoxicity, and apoptosis-resistant tumors
Antioxidant defense research	Glutathione Peroxidase	GPX family, especially GPX4	GSH-dependent antioxidant defense, lipid peroxidation suppression, and ferroptosis regulation
Iron uptake research	Transferrin Receptor	TFRC and iron transport-related targets	Iron uptake, ferroptosis sensitivity, tumor metabolism, and oxidative injury research
Cuproptosis research	Cuproptosis	Copper ion homeostasis and mitochondrial lipoylated protein-related targets	Copper-dependent cell death, mitochondrial metabolism, tumor cell death, and proteotoxic stress research
Paraptosis research	Paraptosis	Non-caspase-dependent cell death-related molecules	Cytoplasmic vacuolization, ER/mitochondrial swelling, apoptosis-resistant models, and alternative death mechanisms
PKD signaling research	PKD	Protein kinase D-related targets	Oxidative stress, mitochondrial function, cell survival/death balance, and signal transduction research

The key to apoptosis research is to distinguish cell death modes, identify pathway sources, and establish a mechanistic closed loop. Only by integrating death receptor, mitochondrial, caspase, Bcl-2 family, p53/IAP regulation, and related indicators of ferroptosis, necroptosis, and pyroptosis can the true mechanism of cell death and its disease significance be accurately determined.

References

[1] Cao L, et al. J Cell Death. 2016 Dec 29;9:19-29.

[2] Dasgupta A, et al. Int J Mol Sci. 2017 Jan;18(1):23.

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