Novel Parkin agonists from Poria cocos against dyslipidemia

Parkin, a cytosolic E3 ubiquitin ligase, plays a crucial role in targeting damaged mitochondria. The dysfunction of Parkin has been implicated in various diseases, including dyslipidemia, highlighting the significance of regulating Parkin activity for therapeutic interventions. Poria cocos (PC), a traditional Chinese medicine with a history spanning over two thousand years, has shown promising effects in regulating dyslipidemia. However, the scarcity of Parkin ligands, particularly from PC, remains a significant drawback in the field. This study identified two novel Parkin ligands from PC using a Parkin-based centrifugal ultrafiltration/liquid chromatography/mass spectrometry method. Molecular docking analysis, molecular dynamic simulations, and autoubiquitination assays confirmed their abilities to activate Parkin. Furthermore, their mitophagy promotion and dyslipidemia mitigation capacities were validated in fat emulsion-induced human liver L02 cells and high-fat diet-induced mice. The results revealed that the two ligands, tumulosic acid and polyporenic acid C, from PC activated Parkin and further promoted mitophagy to alleviate dyslipidemia. These findings will contribute to developing new drugs and enhance our understanding of the PC anti-dyslipidemia mechanisms.