Integrated transcriptomics and metabolomics unravel the key metabolic pathways involved in the therapeutic mechanism of Salvianic acid A against hepatic fibrosis

Abstract

Effective drugs for the clinical treatment of hepatic fibrosis have not yet been identified. Salvianic acid A (SAA) protective mechanisms primarily include anti-inflammation, anti-oxidative stress, and modulation of immune system function. Metabolic dysfunction is well recognized as the driver for hepatic fibrosis. However, the precise action mode and underlying mechanism of SAA in modulating hepatic metabolism to combat hepatic fibrosis remain incompletely understood. This study aimed to investigate the metabolic mechanism by which SAA improves hepatic fibrosis based on metabolomics and transcriptomics profiling. A mouse model of carbon tetrachloride (CCl₄)-induced hepatic fibrosis mouse model was established, and protective effects of SAA were evaluated through pathological characteristics. Integrated metabolomics and transcriptomics analysis revealed three key altered metabolic pathways: bile secretion, carbohydrate digestion and absorption, and regulation of lipolysis in adipocytes. SAA modulated the bile secretion pathway, dependent on reducing water channel protein Aqp1, cholesterol synthesis enzyme Hmgcr and Na⁺/K⁺-ATPase enzyme Atp1a3, accompanied by up-regulating metabolites glutathione and glucose levels. SAA also regulated carbohydrate digestion and absorption by decreasing the glucose homeostasis-related Akt3, essential enzyme G6pc for gluconeogenesis/glycogenolysis and glucose transporter Atp1a3 with a concomitant increase of metabolites D-galactose, maltose, and sucrose levels. Moreover, SAA improved lipolysis in adipocytes in liver fibrosis through inhibiting lipolysis related Prkg1, lipid transporter Fabp4, lipolysis-associated Akt3 and increasing lipolysis mediator Adrb3, along with upregulated levels of metabolites adenosine monophosphate and norepinephrine. In conclusion, SAA alleviates hepatic fibrosis through modulating metabolic disorders, mainly relying on the metabolic improvements of bile secretion, carbohydrate digestion and absorption and adipocyte lipolysis.