Citrinin Induces Hepatic Inflammatory Injury through the PERK-CHOP-NLRP3 Axis-Mediated Pyroptosis

Area of Science:

• Toxicology
• Cell Biology
• Hepatology

Background:

• Citrinin (CTN) is a prevalent food contaminant with known health risks.
• The specific mechanisms of CTN-induced liver injury, particularly concerning endoplasmic reticulum (ER) stress and pyroptosis, are not fully understood.

Purpose of the Study:

• To investigate the role of ER stress-mediated pyroptosis in CTN-induced liver injury.
• To elucidate the molecular pathways involved in CTN hepatotoxicity.

Main Methods:

• In vivo studies using mice and in vitro studies using HL-7702 cells exposed to CTN.
• Analysis of liver injury markers, pro-inflammatory cytokines (IL-1β, IL-18), pyroptosis-related proteins, and ER stress markers (PERK, CHOP).
• Genetic manipulation including silencing CHOP and inhibiting PERK.

Main Results:

• CTN exposure disrupted liver structure, induced hepatocyte damage, and elevated liver injury markers and pro-inflammatory cytokines.
• CTN triggered both ER stress and pyroptosis, with NLRP3 inflammasome activation being central to CTN-induced inflammatory injury in cells.
• The PERK-CHOP pathway was found to regulate NLRP3 inflammasome activation, thereby mediating CTN-induced hepatotoxicity.

Conclusions:

• CTN induces liver injury through a mechanism involving ER stress and NLRP3-dependent pyroptosis.
• The PERK-CHOP pathway plays a critical role in regulating this process.
• The PERK-CHOP-NLRP3 signaling axis represents a potential therapeutic target for mitigating CTN-related liver damage.