Table 1 Caspase-8 in diseases and associated cell death pathways
From: Caspase-8 in inflammatory diseases: a potential therapeutic target
Disease name | The role of caspase-8 in diseases | Cell death pathway involved | References |
|---|---|---|---|
Multiple sclerosis | Caspase-8 exhibits a complex role in MS, with its downregulation promoting necroptotic cell death in cortical neurons and oligodendrocytes, while its upregulation in microglia contributes to inflammation through noncanonical inflammasome activation, highlighting the need for further exploration of its differential effects across cell types | Apoptosis, necroptosis, pyroptosis, and inflammasome activation | |
Inflammatory bowel disease | Caspase-8 plays a dual role in IBD, with both its deficiency and overexpression linked to the disease's progression, highlighting its complex involvement in intestinal inflammation and homeostasis | Apoptosis, necroptosis, pyroptosis, and inflammasome activation | |
Autoimmune lymphoproliferative syndrome | Caspase-8, a crucial mediator of apoptosis in the FAS pathway, is implicated in ALPS through its deficiency, which leads to dysregulated lymphocyte apoptosis and contributes to the disease’s progression, alongside potential involvement in necroptotic cell death | Apoptosis and necroptosis | |
Rheumatoid arthritis | Caspase-8 plays a multifaceted role in RA by modulating inflammatory responses to maintain joint homeostasis, serving as a pivotal biomarker and mediator for ferroptosis and pyroptosis, and enabling the resveratrol-induced apoptosis of fibroblast-like synoviocytes | Necroptosis, ferroptosis, pyroptosis, and apoptosis | |
Autoimmune hepatitis | In AIH, caspase-8 is the primary mediator of cell death through excessive activation of apoptosis, indicating that targeting the caspase-8-mediated extrinsic apoptosis pathway could be a potential therapeutic strategy to protect liver cells, | Apoptosis | [136] |
Sjögren’s syndrome | In SS, caspase-8 is a pivotal mediator of cell death, both through autoantibody-triggered caspase-8 dependent apoptosis and via lysosome-dependent cell death caused by impaired autophagic caspase-8 degradation due to LAMP3 overexpression, underscoring apoptosis and lysosome-dependent pathways as critical mechanisms in the disease’s pathogenesis and potential therapeutic targets | Apoptosis | |
Alzheimer’s disease | Caspase-8 plays a central role in AD by mediating neuronal apoptosis and contributing to the formation of amyloid plaques and neurofibrillary tangles, with its inhibition offering a potential strategy to slow AD progression | Apoptosis, necroptosis, pyroptosis, and inflammasome activation | |
Parkinson’s disease | Caspase-8 plays a critical role in PD by regulating apoptosis, necroptosis, and inflammatory responses, contributing to the progressive loss of dopaminergic neurons and neurodegeneration, making it a potential therapeutic target for PD treatment | Apoptosis, necroptosis, and inflammatory responses | |
Sepsis | Caspase-8 plays a critical role in sepsis by influencing cell death pathways, with elevated levels linked to mortality, and its modulation could serve as a potential therapeutic strategy for managing sepsis and its associated organ dysfunction | Apoptosis, necroptosis, pyroptosis, and inflammasome activation | |
Hepatocellular carcinoma | Caspase-8, a pivotal regulator in both apoptosis and necroptosis pathways, is intricately involved in the modulation of HCC cell death, suggesting that the manipulation of caspase-8 activity could be a strategic approach for selectively targeting HCC cells through distinct cell death mechanisms | Apoptosis and necroptosis | |
Breast cancer | Caspase-8 plays a pivotal role in breast cancer by mediating both extrinsic apoptosis and a noncanonical pyroptosis pathway, where it cleaves GSDMC to induce pyroptosis and tumor necrosis upon TNFα stimulation, and collaborates with PARP inhibitors to sensitize tumor cells to pyroptosis, thereby enhancing cancer cell death and immune response, highlighting its critical involvement in multiple cell death mechanisms in breast cancer | Apoptosis, necroptosis, and pyroptosis | |
Ewing’s sarcoma | Caspase-8 is a crucial mediator in the apoptotic pathways of Ewing’s sarcoma, as it regulates cell survival and proliferation through both extrinsic (Fas and caspase-8) and intrinsic (caspase-9, Bad, Bcl-2, and XIAP) pathways, and serves as a predictive biomarker for sensitivity to death receptor targeted agents like conatumumab, as well as playing a significant role in tumor cell death induced by TRAIL-expressing mesenchymal stem cells | Apoptosis | |
Squamous carcinoma | Caspase-8 plays a pivotal role in the induction of apoptosis in squamous carcinoma cells, particularly in oral squamous cell carcinoma (OSCC), where it is activated by CLEFMA treatment and arsenic compounds, leading to both extrinsic and intrinsic apoptotic pathways, as evidenced by increased cleavage of poly ADP-ribose polymerase and activation of caspase-8, -9, and -3, ultimately contributing to the suppression of tumor growth | Apoptosis | |
Non-small cell lung carcinoma (NSCLC) | Caspase-8 plays a critical role in non-small cell lung carcinoma (NSCLC) by regulating interleukin-8 production, being targeted for activation by HDAC inhibitors to induce apoptosis, and its overexpression along with FLIP correlates with poor prognosis; it is integral to both extrinsic and intrinsic apoptotic pathways in NSCLC | Apoptosis | |
Esophageal cancer | Caspase-8 plays a significant role in esophageal cancer by being involved in the induction of pyroptosis through the PKM2/caspase-8/caspase-3/GSDME axis following photodynamic therapy, while also being bypassed in TRAIL-induced apoptosis resistance mechanisms involving TRADD and c-FLIP, highlighting its involvement in both pyroptosis and apoptosis pathways in this cancer type | Apoptosis and pyroptosis | |
Colorectal cancer | Caspase-8 is a key mediator in colorectal cancer, as it is involved in the induction of apoptosis through the upregulation by sanshools and the sensitization effect of EGCG in combination with TRAIL, while also participating in the NAIP-NLRC4 inflammasome-mediated pyroptosis and inflammation | Apoptosis and pyroptosis | |
Renal cell carcinoma | Caspase-8 plays a critical role in renal cell carcinoma by mediating both apoptosis and pyroptosis, as evidenced by its activation in response to STING depletion, its involvement in TRAIL-induced apoptosis when combined with resveratrol, and its inhibition by miR-381-3p, which also suppresses necroptosis. Additionally, PP5 inhibition leads to the activation of caspase-8 in the extrinsic apoptotic pathway, suggesting its potential as a therapeutic target in RCC | Apoptosis and pyroptosis | |
Rhabdomyosarcoma | In rhabdomyosarcoma, caspase-8 plays a pivotal role in TRAIL-induced apoptosis, as its expression and catalytic activity are both necessary and sufficient for sensitivity to the DR5 antibody drozitumab. This sensitivity leads to the assembly of the death-inducing signaling complex and subsequent activation of the apoptotic pathway, resulting in cell death | Apoptosis | |
Ovarian cancer | Caspase-8 is a pivotal protease in ovarian cancer that orchestrates a delicate balance between apoptotic and nonapoptotic functions, such as cell cycle regulation, invasiveness, metastatic behavior, immune homeostasis, and cytokine production, with its dysregulation leading to increased tumor aggressiveness and immune resistance | Apoptosis | |
Nasopharyngeal carcinoma | Caspase-8 plays a crucial role in the anti-nasopharyngeal carcinoma action of calycosin, as it is identified as a core target in the network pharmacology analysis and validated in human and preclinical studies, with its activation leading to increased apoptosis in nasopharyngeal carcinoma cells | Apoptosis |