Squalene epoxidase (SQLE), an enzyme involved in cholesterol biosynthesis, has a role in the development of hepatocellular carcinoma associated with nonalcoholic fatty liver disease (NAFLD-HCC), according to new research. The study also demonstrates that terbinafine, an approved antifungal agent that targets SQLE, inhibits NAFLD-HCC in cellular and animal models, highlighting its therapeutic potential as a repurposed drug.

With the increasing levels of obesity worldwide, fatty liver disease is becoming a major health problem and an emerging risk factor for liver cancer. Jun Yu and colleagues investigated the molecular mechanisms that underlie NAFLD-HCC, using transcriptome analysis to identify potential gene candidates.

RNA sequencing analysis revealed that SQLE was overexpressed in human NAFLD-HCC tissue and in obesity-associated NAFLD-HCC mouse models. Moreover, SQLE expression was associated with poor survival in patients with hepatocellular carcinoma and confirmed as an independent prognostic factor.

SQLE acted as an oncogene in the context of NAFLD-HCC. SQLE promoted cell growth and inhibited apoptosis in NAFLD-HCC cell lines, and transgenic expression of SQLE specifically in hepatocytes accelerated tumour growth in NAFLD-HCC mouse models. Examining the mechanism of action, the researchers found that SQLE promoted tumorigenesis via regulation of cholesteryl esters and reactive oxygen species. Crucially, pharmacological inhibition of SQLE with terbinafine suppressed NAFLD-HCC growth in vitro and in vivo.

“Epidemiological and preclinical studies have suggested a causative role of cholesterol and its metabolites in cancer development,” explains Yu. “While the majority of published studies focused on HMG-CoA reductase as it is the first rate-limiting enzyme, the role of SQLE on cholesterol homeostasis was frequently ignored.” The researchers plan to optimize the use of terbinafine for the prevention and treatment of NAFLD-HCC, and ultimately hope to translate their experimental work to the clinic.