Epigenetic therapy based on micrornas inhibition for the amelioration of masld phenotype

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most prevalent liver disorder worldwide. In Europe, around 25% of people suffer from this disease. It is strongly associated with several comorbidities, including obesity, type 2 diabetes mellitus, and metabolic syndrome. Additionally, it has a strong association with cardiovascular diseases. Currently, there are no approved drugs for this disease and the need for non-invasive biomarkers and treatments is critical due to the complexity of the disorder. MicroRNAs are small non-coding RNAs which regulate gene expression posttranscriptionally, affecting several physiological and pathological processes. Thus, microRNAs have been suggested as potential biomarkers and therapies for different diseases. Among the several systems to inhibit microRNAs and RNAs, morpholino is a form of antisense RNA inhibition used to block complementary RNA sequences. Considering the potential pathological influence of microRNAs in MASLD, we aimed to discover and describe the role that several microRNAs may have on MASLD, and to assess their inhibition. After extensive screenings, three microRNAs, miR-200b, miR-409 and miR-146b, among others, were found up-regulated in mice fed with choline-deficient, L-amino aciddefined, high-fat diet (CDA-HFD), and their expression was blocked by using in vivo morpholinos. After several analyses, performed on explorative sets of animals, microRNA 200b was selected over the other two and validated in a further cohort of mice. In summary, this study led us to the conclusion that miR-200b was found to be increased in mice fed with CDA-HFD, and that after inhibition of the expression of this microRNA with vivo morpholino injection, an improvement in liver fibrosis was observed. However, it was not sufficient to reverse the liver damage. Further studies are necessary in another animal model but this microRNA could be a potential therapeutic target for MASLD.