Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related deaths worldwide. Despite advancements in antiviral therapies for hepatitis B (HBV) and hepatitis C (HCV), HCC incidence continues to rise due to metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, type 2 diabetes mellitus (T2DM), and emerging environmental and genetic risk factors. Understanding the evolving landscape of HCC pathogenesis is crucial for improved prevention and treatment strategies. OBJECTIVE: This review consolidates recent insights into established and emerging HCC risk factors, highlighting epidemiological trends, molecular mechanisms, and global disparities. It also explores novel therapeutic and preventive strategies aimed at reducing HCC burden and improving patient outcomes. METHODS: A systematic literature review was conducted, incorporating epidemiological studies, molecular research, and clinical trials on HCC risk factors. The interplay between viral hepatitis, metabolic syndrome, environmental toxins, and gut-liver axis dysregulation was analyzed to provide a comprehensive understanding of HCC development. RESULTS: While HBV and HCV remain significant drivers of HCC, metabolic risk factors-including MASLD, obesity, insulin resistance, and T2DM-are increasingly prevalent, particularly in Western populations. Environmental exposures such as aflatoxins, alcohol, smoking, and air pollution further exacerbate disease progression. Gut microbiota dysbiosis has also emerged as a key modulator of hepatic carcinogenesis. Advances in precision medicine, including tyrosine kinase inhibitors (sorafenib, lenvatinib), immune checkpoint inhibitors (nivolumab, pembrolizumab), and gut microbiota-targeted therapies, are transforming HCC management. Early detection is improving through biomarker-driven surveillance and AI-enhanced imaging techniques. CONCLUSION: The shifting epidemiology of HCC necessitates a multidisciplinary approach to prevention, early detection, and treatment. Integrating genomic profiling, biomarker-based risk stratification, and equitable healthcare access will be critical to reducing the global burden of HCC.