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Review
. 2025 Aug 27;18(9):1281.
doi: 10.3390/ph18091281.

Epigenetic Alterations in Hepatocellular Carcinoma: Mechanisms, Biomarkers, and Therapeutic Implications

Adil Farooq Wali  1 , Abid Reza Ansari  2 , Prince Ahad Mir  3 , Mohamed El-Tanani  1 , Rasha Babiker  4 , Md Sadique Hussain  5 , Jasreen Uppal  3 , Asma Ishrat Zargar  6 , Reyaz Hassan Mir  7
Affiliations
Review

Epigenetic Alterations in Hepatocellular Carcinoma: Mechanisms, Biomarkers, and Therapeutic Implications

Adil Farooq Wali et al. Pharmaceuticals (Basel). .

Abstract

Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, continues to pose a significant global health burden due to its high mortality rate. In addition to genetic alterations, epigenetic aberrations, including DNA methylation, histone modifications, chromatin remodeling, and noncoding RNA (ncRNA) dysregulation, play critical roles in HCC initiation and progression. Notably, miR-375 and miR-483-5p are among the most dysregulated miRNAs in HCC, with their altered expression levels closely associated with tumor stage and patient survival. These epigenetic modifications offer promising therapeutic avenues due to their reversibility and dynamic nature. Furthermore, specific epigenetic signatures such as CDH1 promoter hypermethylation and HOTAIR overexpression are being explored as potential biomarkers for early detection and treatment response. In this chapter, we review recent advances in the epigenetic landscape of HCC and discuss their diagnostic and therapeutic implications, highlighting their potential to improve patient outcomes through personalized medicine approaches.

Keywords: DNA methylation; epigenetics; histone methylation; liver damage; ncRNAs (noncoding ribonucleic acid).

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Conflict of interest statement

The authors declare no conflicts of interest, financial or otherwise.

Figures

Figure 1
Figure 1
Integrated roles of major epigenetic mechanisms in hepatocellular carcinoma (HCC). This schematic highlights the interconnected pathways through which DNA methylation, histone modifications, and non-coding RNAs contribute to the regulation of gene expression in HCC. DNA methylation silences tumor suppressor genes, histone modifications influence chromatin accessibility, and non-coding RNAs mediate post-transcriptional gene regulation. Together, these mechanisms disrupt cellular homeostasis and promote tumorigenesis, angiogenesis, and metastasis in HCC. Created in BioRender. Babiker, R. (2025) https://BioRender.com/aoasc7p.
Figure 2
Figure 2
Illustrates the role of non-coding RNAs (ncRNAs) in hepatocellular carcinoma (HCC) development. Non-coding RNAs are divided into small non-coding RNAs (sncRNAs), including siRNA, snoRNA, piRNA, miRNA, and tRNA, and long non-coding RNAs (lncRNAs). Dysregulation of lncRNAs—driven by epigenetic modifications such as histone acetylation and methylation (e.g., LncRNA-LET, H19, and LncRNA-P21)—can suppress the expression of tumor-suppressive miRNAs like miRNA-375. This suppression leads to reduced degradation of oncogenic target mRNAs, promoting tumorigenesis and progression of HCC. Created in BioRender. Babiker, R. (2025) https://BioRender.com/0k3tinh.
Figure 3
Figure 3
Epigenetic biomarkers contributing to the progression and prognosis of hepatocellular carcinoma (HCC). The dysregulation of various non-coding RNAs, including circular RNAs (circRNAs) like circPTGR1, microRNAs (miRNAs) such as miR-483-5p and miR-192, and competing endogenous RNAs (ceRNAs), including LINC01093 and RP11 variants, all of which are associated with poor survival outcomes. Epigenetic silencing of E-cadherin through CDH1 promoter hypermethylation and EMT-related histone modifications promotes metastasis. Upregulation of UCA1 in serum represents a non-invasive diagnostic biomarker for HCC with validated sensitivity and specificity. Additionally, downregulation of GAS5 is linked to hepatic failure, further underscoring the prognostic significance of epigenetic alterations in HCC. Created in BioRender. Babiker, R. (2025) https://BioRender.com/nuyjxx6.
See this image and copyright information in PMC

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