Beyond the Usual Suspects: Hepatitis E Virus and Its Implications in Hepatocellular Carcinoma

SIMPLE SUMMARY: Cancer is a major threat to global health, accounting worldwide for nearly 10 million fatalities in 2020. Importantly, carcinogenesis caused by so-called oncoviruses accounts for approximately 10% of the global cancer burden. Specifically, hepatitis B virus, hepatitis C virus and to a lesser extent hepatitis D virus infection have been recognized to be mainly responsible for the occurrence of hepatocellular carcinoma (HCC). Recent studies have further drawn attention to a long-neglected hepatotropic virus, namely hepatitis E virus (HEV), in the context of HCC. Here, we summarize current epidemiological, clinical and experimental studies to unravel a putative link between HEV and HCC and provide an outlook for future scientific efforts in HEV-related HCC research. ABSTRACT: Hepatitis E virus infections are the leading cause of viral hepatitis in humans, contributing to an estimated 3.3 million symptomatic cases and almost 44,000 deaths annually. Recently, HEV infections have been found to result in chronic liver infection and cirrhosis in severely immunocompromised patients, suggesting the possibility of HEV-induced hepatocarcinogenesis. While HEV-associated formation of HCC has rarely been reported, the expansion of HEV’s clinical spectrum and the increasing evidence of chronic HEV infections raise questions about the connection between HEV and HCC. The present review summarizes current clinical evidence of the relationship between HEV and HCC and discusses mechanisms of virus-induced HCC development with regard to HEV pathogenesis. We further elucidate why the development of HEV-induced hepatocellular carcinoma has so rarely been observed and provide an outlook on possible experimental set-ups to study the relationship between HEV and HCC formation.