Hepatocellular carcinoma (HCC) is the most common sole malignancy of the liver as well as one of the leading causes of cancer-related death throughout the globe. Current epidemiological surveys note a distinct shift in the causes of HCC associated with viral hepatitis to metabolic dysfunction-based steatohepatitis (MASLD), long-term alcohol use and obesity. Therefore, accurate assessment of the molecular basis of hepatocellular carcinoma has grown invaluable in the application of precision-based treatment regimens. This systematic review aims to bring together the current literature on the epidemiology, risk factors, the underlying pathophysiology and treatment options of HCC with increased emphasis on the nascent DNA-based and RNA-based options, which promise to transform care paradigms. We systematically reviewed articles recent published examining genetic approaches related to treatment. Various search engine were accessed via Scopus, ACS Publishing Center, Springer Nature, Bentham Science, PLOS One, and MDPI. Oncogenic alterations and reactivate tumour suppressor pathways via DNA-centric therapeutics by using CRISPR/Cas9 genome editing, TALEN-mediated genome modification, and synthetic lethality of cellular responsiveness to DNA repair vulnerabilities. At the same time, RNA-targeted modalities, which include miRNA, siRNA, mRNA, and saRNA therapeutic agents, demonstrate plausible silencing of oncogenic networks, optimising antitumour immune responses, and the platform-driven target expression of drugs using nanotechnological platforms. Recent information elucidates the complex interplay of genetic vulnerability, metabolic stress and immunosuppressive environments in HCC carcinogenesis. Combinational assessment of nucleic acid-based therapies with immunomodulatory and anti-angiogenic reagents needs to assume priority A convergence between sophisticated genomic editors and RNA therapeutics presents an excellent opportunity to get curative, personalised medicine. Prolonged, consistent, and cross-disciplinary translational studies, linking molecular understanding with clinical options. Bridging molecular insights and clinical advances in hepatocellular carcinoma. DOI:10.1016/j.lddd.2025.100268