N6-Methyladenosine Modification in the Metabolic Dysfunction-Associated Steatotic Liver Disease

Abstract

Epigenetics of N6-methyladenine (m6A) modification may play a key role during the regulation of various diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). The m6A modification has been shown to be accomplished via the exploitation of several players such as methyltransferases, demethylases, and/or methylation-binding molecules. Significantly, the m6A methylation can regulate the key eukaryotic transcriptome by affecting the subcellular localization, splicing, export, stability, translation, and decay of those RNAs. An increasing amount of data has designated that the m6A modification of RNAs can also modulate the expression of autophagy-related genes, which could also control the autophagy in hepatocytes. Oxidative stress with reactive oxygen species (ROS) can induce m6A RNA methylation, which might be associated with the regulation of mitochondrial autophagy (mitophagy) and/or the development of MASLD. Therefore, both autophagy and the m6A modification could play important roles in regulating the pathogenesis of MASLD. Comprehending the relationship between m6A and mitophagy may be helpful for the development of future therapeutic strategies against MASLD. This review would advance the understanding of the regulatory mechanisms of m6A RNA modification, focusing on the impact of mitochondrial dysregulation and mitophagy in the liver with MASLD.

Keywords: MASLD; N6-methyladenine; RNA binding protein; autophagy; liver dysfunction; mitophagy; non-coding RNA; reactive oxygen species.

Figure 1

An illustration of the connection of the m6A-methylated RNAs to various liver disorders. The roles of the alteration of autophagy/mitophagy by the m6A-methylated ncRNAs such as miRNA, lncRNA, and circRNA have been suggested for liver dysfunction such as MASLD, fatty liver disease, liver fibrosis, metabolic dysfunction-associated steatohepatitis (MASH), hepatocellular carcinoma (HCC), and other cancers. The m6A-modified ncRNAs can be diagnostic and/or therapeutic tools for these disorders. The plus sign shows the existence of the modification of m6A in RNAs.

Figure 2

Diagram of the molecules comprising the m6A RNA methylation. The m6A modification is controlled by some methyltransferase “writers” and/or other demethylase “erasers”. Modified m6A-RNA binding proteins with the intracellular signaling function are called “readers”. Instance molecules are shown for each player. Immune stress and/or inflammation with ROS production may influence the function of these molecules. The arrowhead indicates stimulation, whereas the hammerhead denotes inhibition. Note that some critical pathways have been excluded for clarity.

Figure 3

A graphic illustration of the possible tactics against the pathogenesis of MASLD. Some probiotics and/or fecal microbiota transplantation (FMT) may contribute to the modification of the gut microbiota in the host for the adjustment of autophagy/mitophagy as well as the m6A methylation of RNAs, which might be helpful for the treatment of MASLD. The arrowhead shows stimulation. Note that several significant functions such as cytokine induction and/or inflammatory intricate reactions have been lacking for clarity.