Glyco-transformed Gynostemma pentaphyllum extract ameliorates MAFLD by regulating BCAA homeostasis.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become a highly prevalent chronic metabolic disease worldwide. Current clinical drugs are limited by poor long-term efficacy, potential safety risks and high costs. As a popular daily beverage, Gynostemma pentaphyllum exerts prominent hepatoprotective, lipid-regulating and hypoglycemic activities, making it a promising natural agent for MAFLD intervention. In this study, we prepared high-activity secondary gypenosides via snailase-mediated biotransformation, and explored their anti-MAFLD mechanisms through integrated multi-omics analysis and pharmacological validation. The results revealed that snailase efficiently converted primary gypenosides into rare secondary derivatives. Compared with the crude gypenosides from Gynostemma pentaphyllum extract (GYP), the transformed product SGYP exhibited stronger dose-dependent lipid-regulating and anti-inflammatory effects, and effectively alleviated MAFLD-related pathological lesions in mice. Mechanistic investigations demonstrated that SGYP ameliorated high-fat-diet-induced excessive accumulation of branched-chain amino acid (BCAA) in the liver and activated the hepatic AMPK and AKT signaling pathways. Further exogenous BCAA supplementation experiments confirmed that restoring hepatic BCAA homeostasis served as the core mechanism underlying the anti-MAFLD action of SGYP. This study provides an innovative processing technology for the preparation of high-value Gynostemma pentaphyllum products featuring strengthened lipid-lowering, anti-inflammatory activities and prominent hepatoprotective effects.