Establishment and validation of RNA methylation-related lncRNAs signature that predicts prognosis and potential targeted therapy in hepatocellular carcinoma

Abstract Objective Hepatocellular carcinoma (HCC) is a lethal malignancy with limited prognostic biomarkers. This study aimed to develop an RNA methylation-related long non-coding RNA (lncRNA) signature to predict survival and guide therapy in HCC. Methods Transcriptomic and clinical data from 374 HCC tissues (TCGA) were analyzed. RNA methylation-related lncRNAs were identified (Pearson correlation, |cor|> 0.4, p < 0.001). A prognostic signature was constructed using univariate Cox and LASSO regression. Patients were stratified into high-/low-risk groups, validated for survival, immune infiltration, and drug response. Results A robust three-lncRNA signature (SNHG30, AL049840.5, NRAV) was established. High-risk patients showed significantly worse overall survival ( p < 0.001) and progression-free survival ( p < 0.001) compared to low-risk patients. The risk score emerged as an independent prognostic factor (multivariate Cox, p < 0.001) with strong predictive accuracy (1-/3-/5-year AUCs: 0.717/0.686/0.682). Functional analysis revealed distinct biological pathways between risk groups, with high-risk tumors associated with cell cycle dysregulation and immune suppression (higher TIDE scores), while low-risk tumors exhibited metabolic pathway activation. Drug sensitivity analysis suggested differential responses to chemotherapy and targeted therapies between risk groups. Conclusion Our study developed and validated a clinically applicable RNA methylation-related lncRNAs signature that effectively predicts HCC prognosis and therapeutic response. This signature provides valuable insights for risk stratification and may guide personalized treatment decisions in HCC management.