Chebulinic Acid Restores Glycolytic Reprogramming and Mitochondrial Dysfunction in MASLD via Modulation of Lp-PLA2 Signaling.
TL;DR
It is demonstrated that CA improves hepatic metabolic homeostasis through modulation of Lp-PLA2 signaling and significantly ameliorated metabolic dysfunction, hepatic steatosis, inflammation, and oxidative stress in both in vivo and in vitro models.
Abstract
Metabolic dysfunction-associated fatty liver disease (MASLD) is a major global health challenge characterized by metabolic imbalance, inflammation, and oxidative stress, yet effective targeted therapies remain limited. Lipoprotein-associated phospholipase A2 (Lp-PLA2) has emerged as a potential regulator of metabolic disorders, but its role and therapeutic relevance in MASLD remain unclear. Integrative bioinformatics analysis of human liver transcriptomic datasets combined with virtual screening, network pharmacology, and molecular docking identified chebulinic acid (CA) as a potential Lp-PLA2-targeting compound. The therapeutic effects and underlying mechanisms of CA were investigated using high-fat diet (HFD)-induced MASLD mouse models and free fatty acid (FFA)-treated Huh7 hepatocytes using metabolic profiling, histological analysis, Seahorse bioenergetic assessment, adeno-associated virus (AAV)-mediated gene overexpression, and cellular thermal shift assay. Lp-PLA2 was identified as a key regulator associated with MASLD progression and metabolic pathway dysregulation. CA exhibited strong binding affinity to Lp-PLA2 and significantly ameliorated metabolic dysfunction, hepatic steatosis, inflammation, and oxidative stress in both in vivo and in vitro models. Mechanistically, CA restored mitochondrial respiration and glycolytic capacity while reducing abnormal HK2 expression. HK2 overexpression abolished the protective effects of CA, indicating that excessive HK2 expression contributes to metabolic imbalance under metabolic stress conditions. Furthermore, CA CA binding to Lp-PLA2 through the Glu304 residue was required for its metabolic protective effects and was associated with regulation of the Lp-PLA2-HK2-associated pathway. This study identifies Lp-PLA2-associated HK2 dysregulation as a potential contributor to MASLD metabolic dysfunction and demonstrates that CA improves hepatic metabolic homeostasis through modulation of Lp-PLA2 signaling.