The ncRNA-Epigenetic-Cuproptosis Axis in Liver Diseases: From Copper Homeostasis to Precision Hepatology.

Cuproptosis, a recently defined copper-dependent form of regulated cell death driven by excess intracellular copper, is characterized by copper binding to lipoylated tricarboxylic acid (TCA) cycle proteins, causing aberrant protein oligomerization, iron-sulfur cluster loss, and proteotoxic stress. Given the liver's central role in copper homeostasis, hepatocytes are particularly vulnerable to this death modality. This review examines the emerging non-coding RNA (ncRNA)-epigenetic-cuproptosis axis in liver diseases, critically evaluating the evidence across a spectrum from well-established biochemical principles to largely hypothetical connections. Epigenetic mechanisms, including DNA methylation, histone modifications, and N6-methyladenosine (m6A) RNA modifications, can modulate cuproptosis sensitivity. The methyltransferase-like 3 (METTL3)-m6A- fragile X messenger ribonucleoprotein 1 (FMR1)-ferredoxin 1 (FDX1) axis, which confers cuproptosis resistance in hepatocellular carcinoma (HCC) through translational repression of FDX1, represents the strongest mechanistic evidence in hepatic contexts. ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), add additional regulatory layers; miR-133a-5p has been shown to facilitate cuproptosis in hepatocellular carcinoma by targeting ATP7B. We additionally highlight high-copper HCC phenotypes, the MYC-CTR1 and COMMD3 pro-tumor axes, and ferroptosis-cuproptosis combination strategies as priority translational directions. We systematically evaluate the ncRNA-epigenetic-cuproptosis axis across major liver diseases, including metabolic-associated steatotic liver disease, alcohol-associated liver disease, viral hepatitis, cholestatic liver disease, hepatic fibrosis, ischemia-reperfusion injury, Wilson disease, and HCC. Evidence tiers range from direct functional validation, such as copper ionophore-induced cuproptosis in HCC cells and cholestatic liver injury models, through promising but incomplete data, to largely bioinformatic associations lacking functional validation. Translational opportunities include biomarker development, copper ionophore-based therapeutics, and ncRNA-targeted interventions; we further distinguish mechanistic evidence from available human clinical data and outline how tumor copper phenotype, ncRNA signatures, viral etiology, immune context, and individual copper metabolism status could inform precision hepatology. We identify six priority questions and propose a research roadmap to advance this field from correlative associations toward rigorous mechanistic understanding, quantification of cuproptosis relative to established liver-cell death pathways, and eventual clinical implementation in precision hepatology.