Squalene monooxygenase (SQLE) (SQLE)

Squalene monooxygenase (SQLE), also known as squalene epoxidase, is a critical rate-limiting enzyme in the mevalonate pathway, specifically catalyzing the first oxygenation step that converts squalene into 2,3-oxidosqualene [3, 8]. This enzyme is localized to the endoplasmic reticulum and is essential for the biosynthesis of cholesterol in mammals and ergosterol in fungi [5, 9]. SQLE is tightly regulated through both transcriptional control by SREBP2 and post-translational degradation mediated by the E3 ubiquitin ligase MARCH6 in response to cholesterol levels [6, 17]. In various cancers, such as hepatocellular carcinoma and breast cancer, SQLE is frequently overexpressed or amplified, acting as a metabolic oncogene that promotes tumor progression by altering lipid metabolism and activating oncogenic signaling pathways like PI3K/AKT [6, 12, 16]. While SQLE has long been a target for antifungal drugs like terbinafine, it is increasingly recognized as a therapeutic target for hypercholesterolemia and oncology [2, 17]. Inhibitors of mammalian SQLE, such as NB-598, aim to lower cholesterol levels or induce ferroptosis in cancer cells, though challenges remain regarding selectivity and the emergence of constitutively active truncated forms under hypoxic conditions [3, 12, 18].

Other names

Squalene epoxidaseSEERG1EC 1.14.14.17

Inhibition of the catalytic domain of squalene monooxygenase, preventing the conversion of squalene to 2,3-oxidosqualene, thereby disrupting cholesterol biosynthesis and leading to squalene accumulation.