PKM2-mediated STAT3 phosphorylation promotes acute liver failure via regulating NLRP3-dependent pyroptosis

Area of Science:

• Immunology
• Hepatology
• Molecular Biology

Background:

• Acute liver failure (ALF) is a critical condition involving severe inflammation and multi-organ dysfunction.
• Pyruvate kinase M2 (PKM2) has emerged as a potential target for modulating macrophage inflammation in ALF.
• The precise mechanism linking PKM2 to the inflammatory response in ALF remains largely undefined.

Purpose of the Study:

• To elucidate the role of PKM2 in regulating macrophage-mediated inflammation and pyroptosis during ALF.
• To investigate the therapeutic potential of targeting PKM2 in preclinical models of ALF.

Main Methods:

• Utilized a D-galactosamine/LPS-induced mouse model of ALF.
• Employed myeloid cell-specific PKM2 knockout mice.
• Conducted single-cell transcriptome analysis.
• Investigated the effects of pharmacological inhibition of PKM2 nuclear translocation.

Main Results:

• PKM2 knockout in myeloid cells significantly reduced mortality and hepatic injury in ALF mice.
• PKM2 deficiency attenuated NLRP3 inflammasome activation and pyroptosis in liver macrophages.
• Inhibition of PKM2 nuclear translocation, not its glycolytic activity, conferred protection against ALF.
• PKM2 was found to translocate into the nucleus, bind with STAT3, and enhance NLRP3 expression.

Conclusions:

• PKM2 acts as a critical nonmetabolic regulator of NLRP3-mediated pyroptosis in macrophages during ALF.
• Targeting PKM2 nuclear translocation represents a promising therapeutic strategy for ALF treatment.
• This study provides novel insights into the molecular mechanisms underlying ALF pathogenesis.