Decoding DEN-Induced Hepatocellular Carcinoma: Models, Mechanisms, and Ameliorative Strategies in Preclinical Research

Objective: This review focuses specifically on the DEN-induced hepatocellular carcinoma model, with the objectives are to describing the establishment and characterisation of the DEN model, delineating the underlying molecular and cellular mechanisms driving DEN-induced hepatocarcinogenesis, and exploring various ameliorative treatment strategies investigated, including natural products and AgNPs, along with their proposed mechanisms of action. The review also discusses the translational relevance and limitations of the DEN model and outlines future directions in preclinical HCC research aiming to improve therapeutic outcomes. Data sources: DEN, HCC, and hepatocarcinogenesis were among the search terms used to search databases such as PubMed, Google Scholar, and ScienceDirect. After screening abstracts and titles, conference proceedings and commentary were not included. 95 articles and book chapters were included in the final analysis out of 137 sources. Summary: Future preclinical HCC studies employing DEN models will concentrate on overcoming constraints by combining therapies, targeting tumour heterogeneity, and leveraging enhanced drug delivery technologies, dietary restrictions, tumor microenvironment, and multi-omics approaches. Treatment results are improved by the focused, low-toxicity administration of anti-HCC medicines made possible by nanoparticles. Multi-omics technology integration can reveal new therapeutic targets, biomarkers, and mechanisms influencing the course of HCC and the effectiveness of treatment. Conclusion: Because it mimics important aspects of actual HCC, the DEN-induced HCC model has proven essential in studying the course of liver cancer and testing treatments. The model is nevertheless crucial for investigating therapies, particularly in light of developments in omics and nanotechnology that are bringing preclinical findings closer to clinical use. Keywords: DEN (diethylnitrosamine), HCC (hepatocellular carcinoma), CCl4 (carbon tetrachloride), Hepatocarcinogenesis, AgNPs.