Momordicine I Mediates Lipid‐Lowering Effects of Momordica Charantia 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.