The possible protective effect of entacapone on hepatic fibrosis via the fat mass and obesity-associated protein/ N6-methyladenosine/ silent information regulator 1 pathway in a rat model.

The complex molecular pathways behind liver fibrosis (LF) make the existing antifibrotic therapy unsatisfactory. In this work, entacapone's hepatoprotective activity was examined, along with its impact on the hepatic expression of fat mass and obesity-associated protein (FTO), N6-methyladenosine (m6A), and silent information regulator (SIRT)1 in a rat model of LF. LF was induced by carbon tetrachloride (CCl4) in a dose of 2 mL/kg orally twice weekly throughout the study. Three groups of 30 male Wistar rats were created as follows: (1) control group, (2) LF group, and (3) entacapone-pretreated group. Liver/body weight index and liver function tests were measured. Malondialdehyde, superoxide dismutase, and m6A values, as well as FTO and SIRT1 gene expression, were detected in the liver. Liver histopathology and transforming growth factor β immunohistochemical analysis were assessed. Compared with the LF group, the entacapone-pretreated group showed a decrease in oxidative stress in hepatic tissues and improved hepatic function tests. In comparison with the LF group, this was linked to a decrease in FTO gene expression and an increase in SIRT1 gene expression and the percentage of m6A in total RNA. Additionally, the entacapone-pretreated group decreased the amount of collagen fibers and transforming growth factor β expression, improving the histopathological alterations in the liver. In a rat model of LF, entacapone's hepatoprotective effect may be attributed to the alteration of the FTO/m6A/SIRT1 signaling pathway. The current study may offer entacapone as a promising approach for liver protection during fibrosis. SIGNIFICANCE STATEMENT: The current study suggests that entacapone could increase silent information regulator 1 expression through its effect on fat mass and obesity-associated protein and N6-methyladenosine modulation, providing a promising approach for protecting the liver during fibrosis and identifying a potential new molecular target for the prevention of liver fibrosis.