Targeting squalene epoxidase in the treatment of metabolic-related diseases: current research and future directions

Abstract

Metabolic-related diseases are chronic diseases caused by multiple factors, such as genetics and the environment. These diseases are difficult to cure and seriously affect human health. Squalene epoxidase (SQLE), the second rate-limiting enzyme in cholesterol synthesis, plays an important role in cholesterol synthesis and alters the gut microbiota and tumor immunity. Research has shown that SQLE is expressed in many tissues and organs and is involved in the occurrence and development of various metabolic-related diseases, such as cancer, nonalcoholic fatty liver disease, diabetes mellitus, and obesity. SQLE inhibitors, such as terbinafine, NB598, natural compounds, and their derivatives, can effectively ameliorate fungal infections, nonalcoholic fatty liver disease, and cancer. In this review, we provide an overview of recent research progress on the role of SQLE in metabolic-related diseases. Further research on the regulation of SQLE expression is highly important for developing drugs for the treatment of metabolic-related diseases with good pharmacological activity.

Keywords: Cancer; Cholesterol synthesis; Diabetes mellitus; Drug targets; Metabolism; Nonalcoholic fatty liver disease; Obesity; SQLE; SQLE inhibitors.

Figure 1. Cholesterol synthesis pathway centered on SQLE.

This figure illustrates the simplified cholesterol biosynthesis pathway with a focus on SQLE. The pathway features key rate-limiting enzymes, including HMGCR and SQLE. HMGCR catalyzes the conversion of HMG-CoA to MVA. SQLE first converts squalene to 2,3-epoxysqualene. This intermediate then undergoes further enzymatic reactions to eventually produce cholesterol. When lanosterol synthase activity is low, SQLE diverts 2,3-epoxysqualene to dioxidosqualene, which is then converted to 24(S),25-epoxylanosterol and subsequently to 24(S),25-epoxycholesterol. 24(S),25-Epoxycholesterol binds to LXR, activating it and leading to the upregulation of ABCA1, which enhances cholesterol efflux.

Figure 2. Transcriptional, posttranscriptional, and posttranslational regulation of SQLE.

SQLE can be regulated at the transcriptional level by SREBP2, which is a transcription factor involved in cholesterol synthesis and homeostasis. At the posttranscriptional level, gene expression is regulated through interactions between miRNAs/lncRNAs and SQLE mRNAs. At the posttranslational level, SQLE is regulated through cholesterol-dependent feedback mechanisms. The figure is adapted from Zou et al. (2022) with modifications. Created in BioRender.