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Cardiotoxin from Naja atra Activates the NLRP3/Caspase-1/GSDMD Pyroptosis Pathway to Induce Skin Tissue Injury
Nianying Qin1,2,3, Yiling Zhai1,3, Hongying Cao1,3
1Department of Emergency, The First Affiliated Hospital, Guangxi Medical University, Nanning, China.
Plos Neglected Tropical Diseases
|July 13, 2026
Summary
Naja atra cardiotoxin (CTX) triggers skin necrosis via ROS-activated pyroptosis. Inhibiting ROS, NLRP3, or caspase-1 blocks this inflammatory cascade, offering a therapeutic target for snakebite envenomation.
Area of Science:
- Toxicology
- Molecular Biology
- Immunology
Background:
- Naja atra cardiotoxin (CTX) is a key venom component causing local tissue damage and inflammation.
- The precise molecular mechanisms of CTX-induced skin injury are not fully understood.
Purpose of the Study:
- To elucidate the molecular pathways involved in CTX-induced skin necrosis.
- To investigate the role of pyroptosis and its upstream regulators in CTX envenomation.
Main Methods:
- Transcriptome analysis (RNA-seq) of mouse skin post-CTX injection.
- Functional validation using in vitro assays on HaCaT keratinocytes.
- Assessment of cell death, reactive oxygen species (ROS), and inflammatory markers.
- Pharmacological inhibition of key pathway components (NLRP3, caspase-1, ROS).
Main Results:
- RNA-seq identified significant gene expression changes, with the NOD-like receptor signaling pathway and pyroptosis being highly activated.
- CTX induced pyroptotic morphology, increased ROS production, and activated the NLRP3 inflammasome in skin tissue and keratinocytes.
- A hierarchical cascade of ROS → NLRP3 → caspase-1 → GSDMD was confirmed in CTX-treated cells and tissues.
Conclusions:
- CTX induces skin necrosis through ROS-mediated activation of the NLRP3/caspase-1/GSDMD pyroptotic pathway.
- Pharmacological inhibition of this axis significantly reduced CTX-induced damage and inflammation.
- The ROS-NLRP3-caspase-1-GSDMD pathway represents a promising therapeutic target for Naja atra envenomation.
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