Inhibited peroxidase activity of peroxiredoxin 1 by palmitic acid exacerbates nonalcoholic steatohepatitis in male mice.

Summary

PRDX1 peroxidase activity is reduced in NASH, and palmitic acid directly binds PRDX1 to inhibit its activity, worsening disease. Genetic and mechanistic data show PRDX1 protects the liver by limiting ROS signaling; rosmarinic acid binds and activates PRDX1, alleviating NASH in mice.

Key Findings

• Global hepatic PRDX peroxidase activity is reduced in NASH; palmitic acid binds PRDX1 and inhibits its peroxidase activity.
• Hepatic PRDX1 protects against NASH in male mice across three genetic models by scavenging H2O2, suppressing STAT signaling, and preventing PTP oxidation and lipid peroxidation.
• Rosmarinic acid binds PRDX1 (crystal structure), stabilizes the peroxidatic cysteine, activates PRDX1, and alleviates NASH in vivo.

Clinical Implications

While preclinical, targeting PRDX1 peroxidase activity—potentially via optimized PRDX1 agonists—could represent a therapeutic strategy for NASH. Translation requires safety, selectivity, and efficacy studies in humans.

Limitations

• Findings are preclinical and primarily in male mice; human relevance and sex differences remain to be established.
• Selectivity, pharmacokinetics, and safety of PRDX1 agonism (e.g., rosmarinic acid) were not characterized for clinical translation.

Future Directions

Validate PRDX1 agonism in female models and human tissues, develop selective drug-like PRDX1 activators, and assess long-term efficacy and safety in NASH models.