Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 346-357 http://medscipublisher.com/index.php/cge 354 Additionally, combining epigenetic drugs with chemotherapy has been effective in sensitizing HCC cells to standard treatments like 5-Fluorouracil (5-FU) and sorafenib. This approach has the potential to reduce drug resistance and improve the response rates in patients with advanced HCC (Liu et al., 2020). These combination strategies are being actively explored in clinical trials and could become a cornerstone of future HCC management protocols. By integrating DNA methylation-based diagnostics, epigenetic therapies, and combination approaches, researchers and clinicians are developing more precise and effective strategies for tackling HCC. These innovations not only enhance our understanding of liver cancer but also pave the way for improved patient care and personalized treatment options. 7 Challenges and Future Directions Despite significant progress in understanding DNA methylation in hepatocellular carcinoma (HCC), current therapeutic approaches face substantial challenges. For instance, DNA methylation inhibitors like azacitidine and decitabine have shown limited efficacy in treating solid tumors such as HCC, largely due to the complex tumor microenvironment and heterogeneous methylation patterns in solid tumors. Additionally, the high toxicity and side effects associated with epigenetic drugs restrict their broad clinical application, as these therapies can lead to non-specific activation of oncogenes, resulting in unpredictable clinical outcomes. The reversible nature of epigenetic changes means that therapeutic benefits can be transient, with cancer cells potentially reverting to a malignant state after treatment cessation, highlighting the need for combination or maintenance therapies to sustain long-term efficacy. Future research should focus on developing biomarkers that can predict patient responses to DNA methylation inhibitors, enabling personalized medicine approaches that tailor treatments to the specific methylation profiles of individuals. Additionally, the development of next-generation epigenetic drugs is crucial, with an emphasis on greater selectivity and lower toxicity to effectively target specific methylation patterns associated with HCC progression. Integrating multi-omics technologies, such as transcriptomics and proteomics, with DNA methylation studies could help identify novel therapeutic targets and deepen our understanding of the complex relationship between gene expression and methylation, driving further innovation in HCC treatment. The exploration of combination therapy strategies is also emerging as a key area of interest, particularly combining DNA methylation inhibitors with immune checkpoint inhibitors or targeted therapies to enhance overall treatment efficacy. Research indicates that changes in DNA methylation can influence the immune microenvironment of tumors, potentially making them more responsive to immunotherapies. By integrating these combination approaches, there is potential to achieve synergistic effects, enhancing therapeutic outcomes and overcoming resistance mechanisms in HCC. As research advances in precision medicine, improved therapeutic agents, and innovative treatment strategies, the future of HCC management holds promise for significantly better patient outcomes. Acknowledgments We extend our sincere thanks to two anonymous peer reviewers for their invaluable feedback on the initial draft of this paper, whose critical evaluations and constructive suggestions have greatly contributed to the improvement of our manuscript. Conflict of Interest Disclosure The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Arechederra M., Recalde M., Gárate-Rascón M., Fernández-Barrena M.G., Ávila M.A., and Berasain C., 2021, Epigenetic biomarkers for the diagnosis and treatment of liver disease, Cancers, 13(6): 1265. https://doi.org/10.3390/cancers13061265 Cheng J.M., Wei D.K., Ji Y., Chen L.L., Yang L.G., Li G., Wu L.L., Hou T., Xie L., Ding G.H., Li H., and Li Y.X., 2018, Integrative analysis of DNA methylation and gene expression reveals hepatocellular carcinoma-specific diagnostic biomarkers, Genome Medicine, 10(1): 42. https://doi.org/10.1186/s13073-018-0548-z
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