GSDME-Mediated Pyroptosis and the mtDNA-cGAS-STING Pathway Drive Deoxynivalenol-Induced Porcine Intestinal...

Area of Science:

• Toxicology
• Immunology
• Gastroenterology

Background:

• Deoxynivalenol (DON) is a common mycotoxin impacting intestinal health.
• Mechanisms of DON-induced chronic intestinal inflammation are not fully understood.

Purpose of the Study:

• Investigate the molecular mechanisms of DON-induced intestinal inflammation.
• Identify potential therapeutic targets for DON-associated enteropathy.

Main Methods:

• Utilized a 28-day piglet model and porcine intestinal epithelial cells (IPEC-J2).
• Assessed intestinal morphology, inflammation markers, and pyroptosis pathway components.
• Examined mitochondrial integrity, mitochondrial DNA (mtDNA) release, and cGAS-STING pathway activation.
• Employed GSDME knockdown to evaluate its role in DON toxicity.

Main Results:

• DON exposure induced intestinal damage, inflammation, and pyroptosis via the caspase-3/Gasdermin E (GSDME) pathway.
• DON triggered mitochondrial membrane permeabilization, leading to cytosolic mtDNA release.
• Activated mtDNA initiated the cGAS-STING innate immune pathway, amplifying inflammation.
• GSDME knockdown mitigated DON-induced mitochondrial dysfunction, mtDNA leakage, and cGAS-STING activation, reducing intestinal injury.

Conclusions:

• The caspase-3/GSDME pathway is central to DON-induced intestinal inflammation.
• Mitochondrial dysfunction and subsequent mtDNA release activate the cGAS-STING pathway, exacerbating injury.
• Targeting the GSDME/mitochondria/cGAS-STING axis offers a promising strategy for treating mycotoxin-associated enteropathy.