Hepatocellular carcinoma (HCC) is one of the most notable lethal malignancies worldwide. However, the molecular mechanisms involved in the initiation and progression of this disease remain poorly understood. Over the past decade, many studies have demonstrated the important regulatory roles of long non-coding RNAs (lncRNAs) in HCC. Here, we comprehensively review recent discoveries regarding HCC-associated lncRNA functions, which we have classified and described according to their mechanism models.

(1) Background: It is well-known that long non-coding RNAs (lncRNAs) and N7-methylguanosine (m7G) contribute to hepatocellular carcinoma (HCC) progression. However, it remains unclear whether lncRNAs regulating m7G modification could predict HCC prognosis. Thus, we sought to explore the prognostic implications of m7G-related lncRNAs in HCC patients. (2) Methods: Prognostic M7G-related lncRNAs obtained from The Cancer Genome Atlas (TCGA) database were screened by co-expression analysis and univariate Cox regression analysis. Next, the m7G-related lncRNA signature (m7GRLSig) was conducted by Least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression analysis. Kaplan–Meier analysis and time-dependent receiver operating characteristics (ROC) assessed the prognostic abilities of our signature. Univariate and multivariate Cox regression, nomogram, and principal component analysis (PCA) were conducted to evaluate our signature. Subsequently, we investigated the role of m7GRLSig on the immune landscape and sensitivity to drugs in HCC patients. The potential function of lncRNAs obtained from the prognostic signature was explored by in vitro experiments. (3) Results: A novel m7GRLSig was identified using seven meaningful lncRNA (ZFPM2-AS1, AC092171.2, PIK3CD-AS2, NRAV, CASC19, HPN-AS1, AC022613.1). The m7GLPSig exhibited worse survival in the high-risk group and served as an independent prognostic factor. The m7GRLSig stratification was sensitive in assessing the immune landscape and sensitivity to drugs between the high-risk and low-risk groups. Finally, in vitro experiments confirmed that the knockdown of NRAV was accompanied by the downregulation of METTL1 during HCC progression. (4) Conclusions: The m7G-related signature is a potential predictor of HCC prognosis and contributes to individualize the effective drug treatment of HCC.