Ultrasound-targeted Microbubble Destruction Mediated miR-200a/PEG10 Axis Promotes Autophagy to Alleviate MAFLD
TL;DR
The findings indicated that the combined intervention alleviated MAFLD, at least in part, through the promotion of autophagy, and provided a novel therapeutic strategy and a theoretical basis for the development of targeted interventions for MAFLD.
Abstract
This study aimed to explore the therapeutic potential and mechanism of ultrasound-targeted microbubble destruction (UTMD) combined with the miR-200a/PEG10 axis in metabolic-associated fatty liver disease (MAFLD). This study was performed at clinical, cellular, and animal levels. Clinically, liver tissues from 10 MAFLD patients and 10 healthy controls were collected to detect miR-200a/PEG10 expression and their correlation. A cellular MAFLD model was induced by palmitic acid (PA)/oleic acid (OA), followed by rescue experiments to assess lipid accumulation, mitochondrial function, apoptosis, and autophagy-related indicators. Animal MAFLD models were established via a high-fat diet, and corresponding interventions were administered to assess hepatic pathological injury and autophagic status. In patients with MAFLD, PEG10 expression was significantly upregulated, whereas miR-200a was downregulated, and their expression levels were negatively correlated. In both MAFLD cells and mouse models, UTMD combined with miR-200a mimics and siPEG10 significantly alleviated hepatic steatosis, reduced lipid accumulation, improved mitochondrial morphology and function, decreased apoptosis, increased the expression levels of autophagy-related proteins (Beclin1, LC3B, PINK1, and Parkin), and reduced P62 level. Rescue experiments further demonstrated that treatment with the autophagy inhibitor 3-methyladenine (3-MA) aggravated hepatocellular injury, whereas the autophagy activator rapamycin (Rapa) enhanced autophagic activity and ameliorated MAFLD pathology. These findings indicated that the combined intervention alleviated MAFLD, at least in part, through the promotion of autophagy. This study identified the miR-200a/PEG10 axis as a critical regulatory pathway in MAFLD and validated UTMD as an effective gene delivery approach for its modulation. These findings provide a novel therapeutic strategy and a theoretical basis for the development of targeted interventions for MAFLD.