Entacapone Ameliorates MASLD by Inhibiting FTO Demethylase Activity

MASLD is a chronic liver disease characterized by excess fat build up in the liver. Elevated expression of FTO has been implicated in steatosis and MASLD development. There is no standard treatment for MASLD. Here we investigated the hepatoprotective effects of entacapone-a pharmacological inhibitor of FTO-in preclinical models. Entacapone was administered intra-peritoneally at a daily dose of 10 or 30 mg in a MASLD mouse model. Changes in obesity, lipid accumulation and liver fibrosis were monitored during the treatment period. Biomarkers of hepatic and metabolic functions were measured by bioanalyzer. The FTO and metabolic gene transcripts were quantitated by RT-qPCR whereas the m6A levels were measured by ELISA. The hepatic expression of FTO protein in mice and clinical samples (MASLD, MASH and cirrhosis) was visualized by immunohistochemical staining. The regulation of FTO gene by entacapone was also investigated in cell culture. Treatment of mice with entacapone led to a significant reduction in obesity and hepatic fat build-up as well as normalization of metabolic functions and MAS score. The m6A levels in gene transcripts were high and coincided with reduced expression of FTO, lipogenic and inflammatory genes. Interestingly, FTO isoforms FTO-1 FTO-5 and FTO-12 were overexpressed in the MASLD patients whereas no change in FTO-5 and FTO-12 levels was observed in MASH and cirrhosis patients. Further, FTO expression was down-regulated by entacapone in immortalized hepatocytes. This study highlights the therapeutic potential of entacapone in the management of metabolic liver disease by targeting the FTO demethylase activity.