Momordicine I Mediates Lipid‐Lowering Effects of <i>Momordica Charantia</i> L. Triterpenoid Saponins via TFEB‐Driven Lysosomal Biogenesis

Bitter melon saponin extract (BMSE) is well-known to exhibit anti-obesity activity. The network pharmacology study in our previous studies has confirmed that momordicine I was the core triterpenoid compound responsible for the lipid-lowering effects of BMSE, and lipophagy was predicted as the potential mechanism. However, the exact regulatory effects of momordicine I or BMSE on the whole autophagic flux and processes remained unknown. The present study aimed to investigate the specific molecular mechanisms of regulating lipophagy by momordicine I or BMSE in vivo and in vitro. Results demonstrated that both BMSE and momordicine I significantly alleviated lipid accumulation in HepG2 cells and C. elegans, with momordicine I showing a relatively superior effect. Furthermore, treatment with BMSE and momordicine I promoted the formation of autophagosomes, the autophagosomes-lysosome fusions, and autolysosome degradation in HepG2 cells, thereby enhancing autophagic flux. In addition, siRNA interferences and TFEB-deficient C. elegans mutants verified TFEB-mediated lysosomal biogenesis played an essential role in BMSE's effects on lipophagy. Moreover, molecular docking experiments further confirmed that momordicine I could combine TFEB's upstream regulators, AMPK/mTOR, thereby enhancing TFEB nuclear translocation. In summary, BMSE and momordicine I were able to activate the TFEB-mediated lysosomal biogenesis pathway to promote lipophagy and alleviate lipid accumulation.