Natural parkin modulators drive mitophagy and overcome metabolic dysfunction-associated fatty liver disease

Metabolic-associated fatty liver disease (MAFLD) is an increasingly common chronic liver disease currently lacking effective treatments. Mitophagy promotion and subsequent enhancement of mitochondrial quality effectively reduce MAFLD. The PINK1/Parkin pathway is involved in the regulation of mitophagy. Therefore, the aim of this work was to explore the effect of naturally occurring Parkin modulators derived from Sophora flavescens on MAFLD. These regulators, including kushenol I, kurarinone, and kushenol F, effectively targeted the active catalytic center of Parkin, consisting of Ubl, RING1, and IBR, and exerted an exceptional regulation of mitophagy and anti-hepatocellular steatosis effect. A prolonged administration of these Parkin regulators ameliorated systemic metabolic disorders and MAFLD induced by a high-fat diet, as a result of the enhancement of Parkin-mediated mitophagy, which improved mitochondrial quality and promoted mitochondrial biogenesis. The 30-day administration and pharmacokinetic characteristics confirmed the suitability of the modulators for therapeutic use. Thus, these three Parkin modulators exhibited promising anti-MAFLD properties, opening up new possibilities in the development of drugs targeting MAFLD. Three natural Parkin modulators derived from Sophora flavescens effectively target the active catalytic centers of Parkin, such as Ubl, RING1, and IBR, enhancing Parkin-mediated mitochondrial autophagy, thus enhancing mitochondrial quality, and promoting mitochondrial biogenesis to alleviate HFD-induced metabolic-associated fatty liver disease. • Three natural molecules targeted the specific catalytic Parkin centers. • Three molecules mitigated fatty liver by enhancing Parkin-mediated mitochondrial autophagy. • Pharmacokinetic characteristics of the three Parkin modulators were uncovered. • In vivo safety of the three Parkin modulators was evaluated by 30-day administration. • Metabolism and distribution in vivo of the three Parkin modulators were assessed.