Epitranscriptomics in liver disease: Basic concepts and therapeutic potential.

Abstract The development of next-generation sequencing technology and the discovery of specific antibodies targeting chemically modified nucleotides have paved the way for a new era of epitranscriptomics. Cellular RNA is known to dynamically and reversibly undergo different chemical modifications after transcription, such as N 6 -methyladenosine (m6A), N 1 -methyladenosine (m1A), N 6 ,2’-O-dimethyladenosine (m6Am), 5-methylcytosine (m5C), and 5-hydroxymethylcytidine (hm 5 C), whose identity and location comprise the field of epitranscriptomics. Dynamic post-transcriptional modifications determine the fate of target RNAs by regulating various aspects of their processing, including RNA export, transcript processing, splicing, and degradation. The most abundant internal mRNA modification in eukaryotic cells is m6A, which exhibits essential roles in physiological processes, such as embryogenesis, carcinogenesis, and neurogenesis. m6A is deposited by the m6A methyltransferase complex (composed of METTL3/14/16, WTAP, KIAA1429, and RBM15/15B), erased by demethylases (FTO and ALKBH5), and recognized by binding proteins (e.g., YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3). Liver is the largest digestive and metabolic organ, and m6A modifications play unique roles in critical physiological hepatic functions and various liver diseases. This review focuses on the biological roles of m6A RNA methylation in lipid metabolism, viral hepatitis, nonalcoholic fatty liver disease, liver cancer, and tumor metastasis. In addition, we summarize the existing inhibitors targeting m6A regulators and discuss the potential of modulating m6A modifications as a therapeutic strategy.