Forsythoside E Alleviates Liver Injury by Targeting PKM2 Tetramerization to Promote Macrophage M2 Polarization

Area of Science:

• Biochemistry
• Immunology
• Molecular Biology

Background:

• Sepsis-induced liver injury is a critical factor impacting patient outcomes.
• Pyruvate kinase M2 (PKM2) plays a role in cellular metabolism and immune responses.

Purpose of the Study:

• To identify novel therapeutic agents for sepsis-induced liver injury.
• To elucidate the molecular mechanism of action for identified compounds.

Main Methods:

• High-throughput virtual screening, target fishing, and atomic force microscopy (AFM).
• Mutant protein construction, dynamic light scattering (DLS), and fluorescence resonance energy transfer (FRET).
• Seahorse XF metabolic analysis, single-cell multi-modal analysis, and transcriptome sequencing.

Main Results:

• Forsythiaside E (FE) was identified as an allosteric activator of PKM2, promoting its tetramerization by binding to K311.
• FE induced metabolic reprogramming in macrophages, suppressed STAT3 phosphorylation and NLRP3 activation, and promoted M2 anti-inflammatory polarization.
• In vivo studies showed FE alleviated sepsis-induced liver injury without significant multi-organ toxicity.

Conclusions:

• FE alleviates sepsis-induced liver injury by targeting PKM2 tetramerization and modulating macrophage polarization.
• This study proposes a metabolic-epigenetic coordinated regulation strategy for treating sepsis-related liver injury.