Chebulinic Acid Restores Glycolytic Reprogramming and Mitochondrial Dysfunction in MASLD via Modulation of Lp-PLA2...

Area of Science:

• Hepatology
• Biochemistry
• Pharmacology

Background:

• Metabolic dysfunction-associated fatty liver disease (MASLD) presents a significant global health challenge with limited targeted therapies.
• Lipoprotein-associated phospholipase A2 (Lp-PLA2) is implicated in metabolic disorders, but its specific role in MASLD requires elucidation.
• Understanding the molecular mechanisms underlying MASLD is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the role of Lp-PLA2 in MASLD pathogenesis.
• To identify potential therapeutic compounds targeting Lp-PLA2 for MASLD.
• To elucidate the underlying mechanisms by which chebulinic acid (CA) exerts protective effects in MASLD.

Main Methods:

• Integrative bioinformatics analysis, virtual screening, network pharmacology, and molecular docking.
• In vivo studies using high-fat diet-induced MASLD mouse models.
• In vitro studies with free fatty acid-treated Huh7 hepatocytes, including metabolic profiling and Seahorse bioenergetic assessment.

Main Results:

• Lp-PLA2 was identified as a key regulator in MASLD progression and metabolic pathway dysregulation.
• Chebulinic acid (CA) demonstrated strong binding affinity to Lp-PLA2 and ameliorated MASLD hallmarks in vivo and in vitro.
• CA restored mitochondrial respiration and glycolytic capacity by reducing abnormal HK2 expression, mediated through Lp-PLA2 binding.

Conclusions:

• Lp-PLA2-associated HK2 dysregulation contributes to metabolic dysfunction in MASLD.
• Chebulinic acid (CA) improves hepatic metabolic homeostasis by modulating Lp-PLA2 signaling, highlighting its therapeutic potential for MASLD.