Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin...

Area of Science:

• Hepatology
• Cellular Biology
• Molecular Medicine

Background:

• Acute liver failure (ALF) is a critical condition characterized by widespread hepatocyte death, involving ferroptosis and pyroptosis.
• Sirtuin 1 (SIRT1) is a deacetylase involved in various cellular processes, including stress response and metabolism, potentially influencing ALF pathogenesis.

Purpose of the Study:

• To elucidate the relationship between ferroptosis and pyroptosis in ALF.
• To investigate the upstream regulatory mechanisms, particularly the role of SIRT1, in these cell death pathways.

Main Methods:

• Analysis of serum biomarkers (ALT, AST) and liver tissue in ALF patients and a mouse model induced by lipopolysaccharide/D-galactosamine (LPS/D-GalN).
• Assessment of ferroptosis and pyroptosis markers, including protein and mRNA expression of key molecules (SIRT1, p53, GPX4, GSDMD, SLC7A11, ACSL4).
• Experimental manipulation using SIRT1, p53, GPX4 modulators, and Gasdermin D (GSDMD) knockout mice to study pathway inhibition.

Main Results:

• ALF patients and mice exhibited elevated liver enzymes and altered expression of proteins involved in ferroptosis (decreased SIRT1, SLC7A11, GPX4; increased acetylated p53, ACSL4) and pyroptosis (increased GSDMD).
• Inhibition of p53, ferroptosis, or GSDMD, and GSDMD knockout attenuated liver injury and reduced inflammatory cytokine levels.
• SIRT1 activation mitigated liver injury, reduced iron deposition, and normalized levels of key proteins, while SIRT1 inactivation worsened ALF.

Conclusions:

• SIRT1 activation effectively reduces LPS/D-GalN-induced ferroptosis and pyroptosis in ALF.
• The protective effect of SIRT1 is mediated through the inhibition of the p53/GPX4/GSDMD signaling pathway.
• Targeting SIRT1 represents a promising therapeutic strategy for managing acute liver failure.