Clinical Significance of RNA Modifications in Hepatic Fibrosis

Hepatic fibrosis is a progressive wound-healing response to chronic liver injury, driven by excessive deposition of the extracellular matrix (ECM) and activation of hepatic stellate cells. This response is a precursor to cirrhosis, hepatocellular carcinoma, and end-stage liver failure, which have a substantial global health burden and limited therapeutic options. Epitranscriptomics is the study of post-transcriptional RNA modifications and their roles in regulating RNA function, which can influence cellular phenotypes and tissue homeostasis. This review systematically delineates the functional landscape of key RNA modifications, including N 6 -methyladenosine (m 6 A), 5-methylcytosine (m 5 C), and N 4 -acetylcytidine (ac 4 C), in hepatic fibrosis. Beyond the canonical m 6 A axis, we specifically highlight the emerging role of ac 4 C in metabolic reprogramming. We also examine how writers, erasers, and readers modulate core fibrogenic pathways, including transforming growth factor-β signaling, ECM stability, and inflammatory responses. Furthermore, we explore stage-specific regulatory networks and crosstalk between RNA modifications and other epigenetic machinery. Finally, we evaluate the clinical potential of targeting RNA-modifying enzymes and developing methylation-based biomarkers, thus outlining challenges and future directions for targeted antifibrotic therapies.