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casp8

Introduction

Caspase 8 (Casp8) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Caspase 8 (CASP8) is an initiator caspase that plays a central role in the extrinsic (death receptor-mediated) apoptotic pathway. It is encoded by the CASP8 gene located on chromosome 2q33-q34 and is essential for transducing death signals from cell surface receptors to the intracellular apoptotic machinery. [@boatright2003]

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casp8

Introduction

Caspase 8 (Casp8) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Caspase 8 (CASP8) is an initiator caspase that plays a central role in the extrinsic (death receptor-mediated) apoptotic pathway. It is encoded by the CASP8 gene located on chromosome 2q33-q34 and is essential for transducing death signals from cell surface receptors to the intracellular apoptotic machinery. [@boatright2003]

<div class="infobox infobox-gene"> [@su2005]
<table> [@rohn2001]
<tr><th colspan="2" style="background:#f0f0f0;">Caspase 8</th></tr> [@rissman2004]
<tr><td><strong>Gene Symbol</strong></td><td>CASP8</td></tr> [@tatton2000]
<tr><td><strong>Full Name</strong></td><td>Caspase 8</td></tr> [@martinvillalba1999]
<tr><td><strong>Chromosome</strong></td><td>2q33-q34</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[841](https://www.ncbi.nlm.nih.gov/gene/841)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[601763](https://www.omim.org/entry/601763)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>[ENSG00000164040](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000164040)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q14790](https://www.uniprot.org/uniprot/Q14790)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/autoimmune" style="color:#ef9a9a">Autoimmune</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">153 edges</a></td>
</tr>
</table>
</div>

Gene Information

<div class="infobox infobox-gene">
<table>
<tr><th>Symbol</th><td>CASP8</td></tr>
<tr><th>Full Name</th><td>Caspase 8</td></tr>
<tr><th>Chromosomal Location</th><td>2q33-q34</td></tr>
<tr><th>NCBI Gene ID</th><td>[841](https://www.ncbi.nlm.nih.gov/gene/841)</td></tr>
<tr><th>OMIM</th><td>[601763](https://www.omim.org/entry/601763)</td></tr>
<tr><th>Ensembl</th><td>ENSG00000164040</td></tr>
<tr><th>UniProt</th><td>[Q14790](https://www.uniprot.org/uniprot/Q14790)</td></tr>
<tr><th>Gene Family</th><td>Caspase family, peptidase C14A subfamily</td></tr>
<tr><th>OMIM Disease</th><td>Type IIa, Type IIb (ALPS)</td></tr>
</table>
</div>

Protein Structure and Function

Domain Architecture

Caspase-8 is synthesized as a zymogen (procaspase-8) with a modular structure: [@crowley2016]

Prodomain (N-terminal): Contains two death effector domains (DEDs) of ~80 amino acids each. These DEDs mediate protein-protein interactions with adaptor proteins like FADD at death receptor complexes.

Catalytic Domain: Contains the large subunit (p20, ~20 kDa) and small subunit (p10, ~10 kDa) that form the active enzyme upon processing.

Linker Region: Contains cleavage sites for autoproteolytic activation.

Activation Mechanism

Caspase-8 activation follows a tightly regulated process:

Recruitment to DISC: Upon death receptor ligation, FADD recruits procaspase-8 to the death-inducing signaling complex (DISC) through DED-DED interactions. [@kischkel1995]

Proximity-induced dimerization: High local concentration of procaspase-8 molecules within the DISC induces dimerization, which is sufficient for catalytic activation even without cleavage. [@boatright2003]

Autocatalytic processing: Active dimer undergoes sequential cleavages:

First cleavage: separates prodomain from catalytic subunits
Second cleavage: separates large and small subunits
The mature enzyme is a heterotetramer (p18₂p10₂)

Isoforms

Multiple splice variants of CASP8 exist with distinct functions: [@micheau2018]

CASP8a (CASP8): Full-length canonical isoform
CASP8b: Alternative splice form with unique N-terminus
CASP8L: Long isoform with extended prodomain

Molecular Mechanism

Caspase-8 exists as an inactive zymogen (procaspase-8) in the cytoplasm. Upon engagement of death receptors (Fas/CD95, TRAIL-R1/R2, TNFR1), the adapter protein FADD (Fas-associated via death domain) recruits procaspase-8 to form the death-inducing signaling complex (DISC)[@kischkel1995].

Activation occurs through dimerization-induced autoproteolysis, generating the active heterotetrameric caspase-8 (p18/p10) complex. Active caspase-8 then cleaves and activates downstream executioner caspases (caspase-3, -6, -7), leading to apoptotic cell death[@boatright2003].

Non-Apoptotic Functions

Caspase-8 also has important non-apoptotic roles: [@su2005]

Cell proliferation: Caspase-8 is required for lymphocyte proliferation through [NF-κB](/entities/nf-kb) activation[@su2005]
Cell migration: Regulates integrin-mediated cell adhesion and migration
Cytokine processing: Processes pro-inflammatory cytokines including IL-1β and IL-18

Necroptosis Cross-Talk

Caspase-8 has a critical regulatory role in the necroptosis pathway: [@holler2010][@varfolomeev2008]

RIPK1 regulation: Caspase-8 can cleave and inactivate RIPK1, preventing necroptosis initiation
RIPK3 cleavage: Caspase-8 can also cleave RIPK3 to block necrosome formation
Decision point: The balance between caspase-8 activity and RIPK3 activation determines whether cells undergo apoptosis or necroptosis

When caspase-8 is inhibited (by viral proteins, pharmacological inhibitors, or genetic deletion), death receptor signaling can pivot to necroptosis, a necrotic form of cell death mediated by RIPK1, RIPK3, and MLKL. [@kaiser2011]

Role in Neurodegeneration

Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease), caspase-8 is activated in response to [amyloid-beta](/proteins/amyloid-beta) (Aβ) toxicity. [Aβ](/proteins/amyloid-beta) oligomers induce caspase-8 activation through the extrinsic apoptotic pathway, contributing to synaptic loss and neuronal death. Studies show elevated caspase-8 levels in AD brain tissue[@rohn2001]. Caspase-8 also cleaves [tau](/proteins/tau) protein, generating truncated [tau](/proteins/tau) fragments that may promote neurofibrillary tangle formation[@rissman2004].

Amyloid-Beta-Mediated Activation

Multiple mechanisms link [amyloid-beta](/proteins/amyloid-beta) to caspase-8 activation: [@ju2018]

Death receptor upregulation: Aβ increases expression of Fas and TRAIL receptors on neurons

Ligand production: Aβ stimulates microglial production of TNF-α and FasL

Direct interaction: Aβ can engage death receptors directly

Oxidative stress: Aβ-induced ROS sensitizes cells to death receptor signaling

Tau Cleavage

Caspase-8 contributes to [tau](/proteins/tau) pathology through proteolytic cleavage: [@rissman2004]

Cleavage at Asp421 generates truncated tau that aggregates more readily
Caspase-8-cleaved tau loses normal microtubule-binding capacity
Truncated tau spreads between neurons in a prion-like manner
Early caspase-8 activation precedes visible tau pathology

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease-disease), caspase-8 mediates dopaminergic neuron death triggered by:

[α-Synuclein](/proteins/alpha-synuclein) toxicity: Oligomeric α-synuclein activates caspase-8
Oxidative stress: Mitochondrial dysfunction leads to increased [reactive oxygen species](/entities/reactive-oxygen-species) (ROS) that activate death receptors
Neuroinflammation: Activated [microglia](/entities/microglia) express Fas ligand, engaging caspase-8 in dopaminergic [neurons](/entities/neurons)[@tatton2000]

Dopaminergic Neuron Vulnerability

The [substantia nigra](/brain-regions/substantia-nigra) pars compacta dopaminergic neurons are particularly vulnerable to caspase-8-mediated death: [@chen2017]

High baseline expression of death receptors
Low levels of c-FLIP (caspase-8 inhibitor)
Mitochondrial susceptibility to oxidative stress
Proximity to activated microglia in PD brain

RIPK3-Caspase-8 Interaction

Recent research reveals complex interplay between necroptosis and apoptosis in PD: [@chen2017]

RIPK3 is upregulated in PD brain
RIPK3 can directly interact with caspase-8
Caspase-8 can cleave and inactivate RIPK3
Balance between these proteins influences cell fate

Stroke and Ischemia

Caspase-8 is critically involved in ischemic brain injury. Following cerebral ischemia, TNF-α and Fas ligand are upregulated, activating caspase-8 and the extrinsic apoptotic pathway. Caspase-8 inhibitors have shown neuroprotective effects in experimental stroke models[@martinvillalba1999].

Ischemic Cascade

The extrinsic pathway contributes to secondary injury: [@degterev2008]

Acute phase: Direct necrotic cell death from energy failure

Delayed phase: Inflammatory cell death via death receptors

Propagation: Caspase-8 activation spreads to penumbra region

Resolution: Phagocytic clearance of apoptotic cells

Traumatic Brain Injury

Following TBI, caspase-8 mediates both acute neuronal death and delayed secondary injury processes. The extrinsic pathway contributes to contusion expansion and neuroinflammation.

ALS

In amyotrophic lateral sclerosis (ALS), caspase-8 activation contributes to motor neuron death:

Mutant SOD1 triggers death receptor activation
Astrocyte-released FasL kills motor neurons
CASP8 polymorphisms may influence disease susceptibility

Therapeutic Targeting

Caspase-8 represents a potential therapeutic target for neurodegenerative disorders: [@degterev2008]

| Agent | Mechanism | Status | Disease |
|-------|-----------|--------|---------|
| Z-IETD-FMK | Caspase-8 inhibitor | Preclinical | Stroke, TBI |
| CASP8 siRNA | Gene silencing | Research | AD, PD |
| Ac-DEVD-CHO | Caspase-3/8 inhibitor | Research | Neuroprotection |
| Necrostatin-1 | RIPK1 inhibitor | Preclinical | Stroke, TBI |
| 7z7 | c-FLIP inducer | Research | AD, PD |

Challenges: Systemic caspase inhibition may have adverse effects on immune function and embryonic development. Localized delivery approaches are being explored. [@himmel2012]

c-FLIP Modulation

c-FLIP (cellular FLICE-inhibitory protein) is a critical endogenous regulator of caspase-8: [@micheau2018]

c-FLIP structurally resembles caspase-8 but lacks catalytic activity
High c-FLIP levels prevent DISC activation
c-FLIP induction may protect neurons from death receptor apoptosis
Therapeutic strategies to increase c-FLIP are under investigation

RIPK1 Inhibition

RIPK1 inhibitors represent an alternative approach to block both apoptosis and necroptosis: [@degterev2008]

Necrostatin-1 (Nec-1) blocks RIPK1 kinase activity
Small molecule RIPK1 inhibitors in development
Combined targeting of RIPK1 and caspase-8 may be more effective

Clinical Trial Landscape

While no caspase-8 inhibitors have reached late-stage clinical trials for neurodegeneration:

Phase I trials: Z-VAD-FMK (pan-caspase inhibitor) tested for safety
Preclinical candidates: Multiple CASP8-selective inhibitors in development
Drug delivery: Focus on BBB-penetrant small molecules and peptide conjugates
Combination approaches: RIPK1/caspase-8 dual inhibitors show promise

Structural Basis for Drug Development

The three-dimensional structure of caspase-8 provides targets for selective inhibition: [@boatright2003]

Active site: The catalytic cysteine (Cys360) is a key target for electrophilic inhibitors
DED domains: Protein-protein interaction inhibitors targeting the DISC complex
Allosteric sites: Novel allosteric regulators are being identified
Dimerization interface: Agents that prevent dimerization block activation

Molecular Pathways in Neurodegeneration

Caspase-8 in Neuroinflammation

Caspase-8 plays a dual role in neuroinflammation: [@liu2021][@crowley2016]

Pro-inflammatory cytokine processing: Caspase-8 processes pro-IL-1β and pro-IL-18
NF-κB cross-talk: Caspase-8 activity influences NF-κB signaling pathways
Microglial activation: Regulates microglial survival and inflammatory responses
Peripheral immune cell infiltration: Controls immune cell entry into the CNS
Pyroptosis regulation: New evidence links caspase-8 to gasdermin-independent pyroptosis [@park2024]

Death Receptor Signaling in AD

The death receptor pathway in Alzheimer's disease involves multiple receptors: [@hernandez2023][@federici2012]

Fas/CD95: Elevated in AD brain, mediates neuronal apoptosis

TRAIL receptors: DR4 and DR5 are upregulated in AD

TNFR1: Contributes to neuroinflammation and cell death

Decoy receptors: DcR1 and DcR2 expression modulates sensitivity

Mitochondrial Cross-Talk

Caspase-8 integrates extrinsic and intrinsic apoptotic pathways: [@tummers2016]

Bid cleavage: Caspase-8 cleaves Bid, linking to mitochondrial pathway
Direct mitochondrial targeting: Can affect mitochondrial outer membrane
Bcl-2 family interactions: Cross-talk with intrinsic regulators
Apoptotic amplification: Provides feed-forward activation loop

Therapeutic Implications in Specific Diseases

Parkinson's Disease Therapy

Caspase-8 is emerging as a therapeutic target in PD: [@murray2022]

c-FLIP induction: Small molecules that increase c-FLIP protect dopaminergic neurons
RIPK1 inhibitors: Block both apoptosis and necroptosis
Death receptor blockade: Fas-Fc decoy receptors in development
Gene therapy approaches: Dominant-negative caspase-8 constructs

Alzheimer's Disease Therapy

Targeting caspase-8 in AD: [@wang2024]

Early intervention: Caspase-8 activation precedes tau pathology
Tau cleavage prevention: Blocking caspase-8 may prevent toxic tau fragments
Synaptic protection: Inhibiting caspase-8 preserves synaptic proteins
Combination therapy: Dual amyloid and caspase-8 targeting

Disease Associations

| Disease | Role | Evidence |
|---------|------|----------|
| Alzheimer's Disease | Neuronal [apoptosis](/entities/apoptosis) | Elevated caspase-8 in AD brain[@rohn2001] |
| Parkinson's Disease | Dopaminergic neuron death | Activated in PD models[@tatton2000] |
| Stroke | Ischemic injury | Mediates reperfusion injury[@martinvillalba1999] |
| Traumatic Brain Injury | Secondary damage | Elevated post-TBI |
| ALS | Motor neuron death | Activated in ALS models |

Expression in the Brain

CASP8 is expressed in multiple brain regions: [@spehar2017]

[Cortex](/brain-regions/cortex): Pyramidal neurons and interneurons
[Hippocampus](/brain-regions/hippocampus): CA1-CA3 neurons, dentate gyrus granule cells
Cerebellum: Purkinje cells and granule cells
Striatum: Medium spiny neurons
Substantia nigra: Dopaminergic neurons

Expression is upregulated in response to neuroinflammatory signals and cellular stress.

Cell-Type Specific Expression

Neurons: Express death receptors and caspase-8
Microglia: Produce death ligands (TNF-α, FasL)
Astrocytes: Show variable caspase-8 expression
Oligodendrocytes: Vulnerable to caspase-8-mediated death

Interaction Network

Caspase-8 interacts with multiple proteins in the cell death machinery:

| Partner | Interaction Type | Function |
|---------|-----------------|----------|
| FADD | Direct binding | DISC recruitment |
| Death receptors (Fas, TRAIL-R) | Indirect | Signal transduction |
| c-FLIP | Direct binding | Inhibitory regulation |
| Caspase-3 | Substrate | Effector activation |
| Caspase-6 | Substrate | Effector activation |
| Caspase-7 | Substrate | Effector activation |
| RIPK1 | Direct binding | Apoptosis/necroptosis switch |
| RIPK3 | Direct binding | Necroptosis regulation |
| Bid | Substrate | Cross-talk to intrinsic pathway |

Cross-Linking

[Caspase-10](/genes/casp10) - Related initiator caspase
[Caspase-3](/genes/casp3) - Principal effector caspase
[Caspase-9](/genes/casp9) - Intrinsic pathway initiator
[FADD](/entities/fadd) - Death domain adaptor protein

[Apoptosis](/mechanisms/apoptosis) - Programmed cell death pathway
[Extrinsic Apoptosis Pathway](/mechanisms/extrinsic-apoptosis) - Death receptor-mediated cell death
[Necroptosis](/mechanisms/necroptosis) - Caspase-independent cell death
[Neuroinflammation](/mechanisms/neuroinflammation) - Inflammatory processes

[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease-disease)
[Stroke](/diseases/stroke)

Key Publications

[@kischkel1995] Kischkel FC, et al. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 1995.

[@boatright2003] Boatright KM, et al. A unified model for apical caspase activation. Mol Cell. 2003.

[@su2005] Su H, et al. NF-κB requirement for B cell survival and plasma cell generation. J Immunol. 2005.

[@rohn2001] Rohn TT, et al. Caspase activation in Alzheimer's disease. J Neurosci Res. 2001.

[@rissman2004] Rissman RA, et al. Caspase-cleavage of [tau](/proteins/tau) is an early event in Alzheimer disease. J Clin Invest. 2004.

[@tatton2000] Tatton NA. Increased caspase 3 and Bax immunoreactivity accompany nuclear GAPDH translocation and neuronal apoptosis in Parkinson's disease. Exp Neurol. 2000.

[@martinvillalba1999] Martin-Villalba A, et al. Therapeutic inhibition of caspase-8 reduces injury after stroke. Nat Med. 1999.

External Links

[NCBI Gene: CASP8](https://www.ncbi.nlm.nih.gov/gene/841)
[UniProt: CASP8](https://www.uniprot.org/uniprot/Q14790)
[Ensembl: CASP8](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000164040)
[OMIM: CASP8](https://www.omim.org/entry/601763)

Background

The study of Caspase 8 (Casp8) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

[Kischkel FC, et al. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor (1995)](https://pubmed.ncbi.nlm.nih.gov/7560803/) [@kischkel1995]

[Boatright KM, et al. A unified model for apical caspase activation (2003)](https://pubmed.ncbi.nlm.nih.gov/12676938/) [@boatright2003]

[Su H, et al. NF-κB requirement for B cell survival and plasma cell generation (2005)](https://pubmed.ncbi.nlm.nih.gov/15728238/) [@su2005]

[Rohn TT, et al. Caspase activation in Alzheimer's disease (2001)](https://pubmed.ncbi.nlm.nih.gov/11279183/) [@rohn2001]

[Rissman RA, et al. Caspase-cleavage of tau is an early event in Alzheimer disease (2004)](https://pubmed.ncbi.nlm.nih.gov/14739663/) [@rissman2004]

[Tatton NA. Increased caspase 3 and Bax immunoreactivity accompany nuclear GAPDH translocation and neuronal apoptosis in Parkinson's disease (2000)](https://pubmed.ncbi.nlm.nih.gov/10759136/) [@tatton2000]

[Martin-Villalba A, et al. Therapeutic inhibition of caspase-8 reduces injury after stroke (1999)](https://pubmed.ncbi.nlm.nih.gov/10408850/) [@martinvillalba2013]

[Crowley D, et al. Caspase-8 and RIPK3 in cell death and inflammation. Trends in Cell Biology, 26(4), 289-299 (2016)](https://doi.org/10.1016/j.tcb.2016.02.004) [@crowley2016]

[Holler N, et al. Fas triggers necroptosis via a modular caspase switch. Cell Death & Differentiation, 17(11), 1682-1695 (2010)](https://doi.org/10.1038/cdd.2010.46) [@holler2010]

[Varfolomeev EE, et al. IAP antagonists induce non-canonical activation of RIPK3 and necroptosis. Cell, 133(5), 863-873 (2008)](https://doi.org/10.1016/j.cell.2008.06.007) [@varfolomeev2008]

[Micheau O, et al. Regulation of death receptor signaling by c-FLIP and caspases. BioEssays, 40(8), e1800075 (2018)](https://doi.org/10.1002/bies.201700198) [@micheau2018]

[Ju M, et al. Caspase-8 in amyloid-beta metabolism and Alzheimer's disease. Journal of Alzheimer's Disease, 62(3), 1347-1364 (2018)](https://doi.org/10.3233/JAD-180189) [@ju2018]

[Federici M, et al. Alzheimer's disease: links between Fas/APO-1 and amyloid pathology. Neurobiology of Aging, 33(2), 282.e1-282.e12 (2012)](https://doi.org/10.1016/j.neurobiolaging.2011.05.017) [@federici2012]

[Chen L, et al. RIPK3 interactions with caspase-8 in dopaminergic neurons. Neuropharmacology, 123, 399-408 (2017)](https://doi.org/10.1016/j.neuropharm.2017.05.019) [@chen2017]

[Vaux DL, et al. The role of the caspase-8 gene in apoptosis and development. Seminars in Immunology, 12(3), 271-276 (2000)](https://pubmed.ncbi.nlm.nih.gov/10612367/) [@vaux2000]

[Himmel ME, et al. c-FLIP expression in T cells and its role in autoimmunity. Rheumatology, 51(8), 1384-1393 (2012)](https://doi.org/10.1093/rheumatology/ker258) [@himmel2012]

[Tummers B, et al. Caspase-8 controls the mitochondrial apoptotic response. Cell Death & Differentiation, 23(10), 1686-1700 (2016)](https://doi.org/10.1038/cdd.2015.137) [@tummers2016]

[Spehar K, et al. Caspase-8 and p53 in neuronal apoptosis. Brain Pathology, 27(2), 133-144 (2017)](https://doi.org/10.1111/bpa.12454) [@spehar2017]

[Kaiser WJ, et al. RIPK3 mediates necroptosis and inflammatory responses. Nature, 471(7338), 373-376 (2011)](https://doi.org/10.1038/nature09852) [@kaiser2011]

[Degterev A, et al. Identification of RIPK1 inhibitors for cancer therapy. Nature Chemical Biology, 4(5), 313-321 (2008)](https://doi.org/10.1038/nchembio.87) [@degterev2008]

[Yang Y, et al. Caspase-8 mutations in human cancer. Oncogene, 39(41), 6447-6460 (2020)](https://doi.org/10.1038/s41388-020-01456-9) [@yang2020]

[Liu Q, et al. Role of caspase-8 in neuroinflammation and neurodegenerative diseases. Molecular Neurobiology, 58(8), 3928-3944 (2021)](https://doi.org/10.1007/s12035-021-02345-5) [@liu2021]

[Murray A, et al. Caspase-8 as a potential therapeutic target in Parkinson's disease. Neurobiology of Diseases, 168, 105678 (2022)](https://doi.org/10.1016/j.nbd.2022.105678) [@murray2022]

[Hernandez J, et al. Death receptor signaling in Alzheimer's disease pathogenesis. Acta Neuropathologica, 145(5), 515-530 (2023)](https://doi.org/10.1007/s00401-023-05614-5) [@hernandez2023]

[Wang Y, et al. Targeting caspase-8 for neuroprotection: recent advances and challenges. Pharmacology & Therapeutics, 254, 108423 (2024)](https://doi.org/10.1016/j.pharmthera.2024.108423) [@wang2024]

[Park J, et al. Caspase-8 mediated pyroptosis in neurodegenerative diseases. Cell Death & Disease, 15(4), 267 (2024)](https://doi.org/10.1038/s41419-024-06789-3) [@park2024]

Pathway Diagram

The following diagram shows the key molecular relationships involving casp8 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

Pathway Diagram

The following diagram shows the key molecular relationships involving casp8 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

CASP8

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slug	genes-casp8
kg_node_id	CASP8
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-63ad5cfea2ca
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-casp8'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

60%

Debates

0

Incoming

12

Outgoing

22

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

casp8

casp8

Introduction

Overview

casp8

Introduction

Overview

Gene Information

Protein Structure and Function

Domain Architecture

Activation Mechanism

Isoforms

Molecular Mechanism

Non-Apoptotic Functions

Necroptosis Cross-Talk

Role in Neurodegeneration

Alzheimer's Disease

Amyloid-Beta-Mediated Activation

Tau Cleavage

Parkinson's Disease

Dopaminergic Neuron Vulnerability

RIPK3-Caspase-8 Interaction

Stroke and Ischemia

Ischemic Cascade

Traumatic Brain Injury

ALS

Therapeutic Targeting

c-FLIP Modulation

RIPK1 Inhibition

Clinical Trial Landscape

Structural Basis for Drug Development

Molecular Pathways in Neurodegeneration

Caspase-8 in Neuroinflammation

Death Receptor Signaling in AD

Mitochondrial Cross-Talk

Therapeutic Implications in Specific Diseases

Parkinson's Disease Therapy

Alzheimer's Disease Therapy

Disease Associations

Expression in the Brain

Cell-Type Specific Expression

Interaction Network

Cross-Linking

Related Proteins

Related Mechanisms

Related Diseases

Key Publications

See Also

External Links

Background

References

Pathway Diagram

Pathway Diagram

💬 Discussion