Squalene epoxidase (also known as squalene monooxygenase, EC 1.14.99.7) is a key rate-limiting enzyme in cholesterol biosynthesis. Anil Padyana and colleagues report the long awaited structure of human squalene epoxidase (SQLE). They solved the crystal structure of the catalytic domain of human SQLE alone and in complex with two similar pharmacological inhibitors and elucidate their mechanism of action. SQLE is the target of fungicides and of increasing interest in human health and disease, particularly as a new anti-cancer target. Indeed, in a companion paper, Christopher Mahoney and colleagues performed an inhibitor screen with cancer cell lines and identified SQLE as an unique vulnerability in a subset of neuroendocrine tumours, where SQLE inhibition caused a toxic accumulation of the substrate squalene. The SQLE structure will facilitate the development of improved inhibitors. Here, we comment on these two studies in the wider context of the field and discuss possible future directions.

角鲨烯环氧酶（也称为角鲨烯单加氧酶，EC 1.14.99.7）是胆固醇生物合成中的关键限速酶。Anil Padyana及其同事报告了人们期待已久的人类角鲨烯环氧酶（SQLE）结构。他们将人类SQLE的催化结构域的晶体结构与两种类似的药理抑制剂一起解决，并阐明了它们的作用机理。SQLE是杀真菌剂的目标，并且对人类健康和疾病的兴趣日益增加，尤其是作为新的抗癌目标。确实，在一篇伴随论文中，克里斯托弗·马洪尼（Christopher Mahoney）及其同事对癌细胞系进行了抑制剂筛选，并将SQLE确定为神经内分泌肿瘤子集中的一个独特漏洞，其中SQLE抑制导致底物角鲨烯有毒积聚。SQLE结构将促进改进抑制剂的开发。在这里，我们将在该领域的更广泛背景下对这两项研究进行评论，并讨论可能的未来方向。