| Summary: | The incidence of hepatocellular carcinoma (HCC) and the mortality resulting from HCC are both increasing. Most patients with HCC are diagnosed at advanced stages when curative treatments are impossible. Current drug therapy extends mean overall survival by only a short period of time. Genetic mutations associated with HCC vary widely. Therefore, transgenic and mutant animal models are needed to investigate the molecular effects of specific mutations, classify them as drivers or passengers, and develop targeted treatments. Cirrhosis, however, is the premalignant state common to 90% of HCC patients. Currently, no specific therapies are available to halt or reverse the progression of cirrhosis to HCC. Understanding the genetic drivers of HCC as well as the biochemical, mechanical, hormonal, and metabolic changes associated with cirrhosis could lead to novel treatments and cancer prevention strategies. Although additional therapies recently received Food and Drug Administration approval, significant clinical breakthroughs have not emerged since the introduction of the multikinase inhibitor sorafenib, necessitating alternate research strategies. Zebrafish (Danio rerio) are effective for disease modeling because of their high degree of gene and organ architecture conservation with human beings, ease of transgenesis and mutagenesis, high fecundity, and low housing cost. Here, we review zebrafish models of HCC and identify areas on which to focus future research efforts to maximize the advantages of the zebrafish model system. Keywords: Cirrhosis, Tumor Microenvironment, Model Organisms, Inflammation, Drug-Induced Liver Injury, Autophagy
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