Cordycepin alleviates metabolic dysfunction-associated liver disease by restoring mitochondrial homeostasis and reducing oxidative stress via Parkin-mediated mitophagy.

Abstract

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) keeps rising with only a few drugs available. The present study aims to investigate the effects and mechanisms of cordycepin on MASLD. Male C57BL/6 mice were induced with a 90-day high-fat diet (HFD) and intraperitoneal administration with streptozotocin to establish MASLD murine model. Then they were randomly divided into the HFD and cordycepin groups (15, 30, 45 mg/kg). Cordycepin was orally given for 30 days. Serum total cholesterol (TC), triacylglyceride (TG), and aspartate aminotransferase (AST) levels were measured. L02 cells were induced by oleate acid (OA) or lipopolysaccharides (LPS), and treated with cordycepin or combined with inhibitors including chloroquine, 3-Methyladenine, and compound C. Atg7 and Parkin were knocked down in L02 cells using siRNA. Oil Red O and Nile Red staining for measuring lipid deposition. Mitochondria were visualized by transfection with mCherry-TOMM20-N10. Quantitative real-time PCR, Western blotting, and immunofluorescence staining were used to determine expressions of key molecules in inflammation, lipid metabolism, mitochondria homeostasis, and oxidative stress. Cordycepin significantly mitigated lipid deposition and ballooning in the livers of MASLD mice. Serum TC, TG, and AST levels were decreased by cordycepin. Cordycepin alleviated OA-induced lipid deposition and LPS-induced inflammation in L02 cells, attenuated oxidative stress, promoted autophagy, and maintained the autophagic flux by activating AMP-activated protein kinase (AMPK). Cordycepin reduced the accumulation of impaired mitochondria by enhancing Parkin-dependent mitophagy and promoting mitochondrial biogenesis. Cordycepin alleviates MASLD by restoring mitochondrial homeostasis and reducing oxidative stress via activating the Parkin-mediated mitophagy.