Epitranscriptomics in liver disease: Basic concepts and therapeutic potential

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 N⁶-methyladenosine (m⁶A), N¹-methyladenosine, N⁶,2'-O-dimethyladenosine, 5-methylcytosine, and 5-hydroxymethylcytidine, 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 recognised by binding proteins (e.g., YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3). The 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, non-alcoholic fatty liver disease, liver cancer, and tumour metastasis. In addition, we summarise the existing inhibitors targeting m⁶A regulators and discuss the potential of modulating m⁶A modifications as a therapeutic strategy.