SARS-CoV-2 infection has led to a global health crisis, and yet our understanding of the disease and potential treatment options remains limited. The infection occurs through binding of the virus with angiotensin converting enzyme 2 (ACE2) on the cell membrane. Here, we established a screening strategy to identify drugs that reduce ACE2 levels in human embryonic stem cell (hESC)-derived cardiac cells and lung organoids. Target analysis of hit compounds revealed androgen signaling as a key modulator of ACE2 levels. Treatment with antiandrogenic drugs reduced ACE2 expression and protected hESC-derived lung organoids against SARS-CoV-2 infection. Finally, clinical data on COVID-19 patients demonstrated that prostate diseases, which are linked to elevated androgen, are significant risk factors and that genetic variants that increase androgen levels are associated with higher disease severity. These findings offer insights on the mechanism of disproportionate disease susceptibility in men and identify antiandrogenic drugs as candidate therapeutics for COVID-19.

SARS-CoV-2感染已导致全球性健康危机，但我们对疾病和潜在治疗方案的了解仍然有限。感染是通过病毒与细胞膜上的血管紧张素转化酶2（ACE2）结合而发生的。在这里，我们建立了筛选策略，以鉴定可降低人胚胎干细胞（hESC）衍生的心脏细胞和肺类器官中ACE2水平的药物。对命中化合物的目标分析表明，雄激素信号是ACE2水平的关键调节剂。用抗雄激素药物治疗可降低ACE2表达，并保护源自hESC的肺类器官免受SARS-CoV-2感染。最后，有关COVID-19患者的临床数据表明，前列腺疾病与雄激素升高有关，是重要的危险因素，而增加雄激素水平的遗传变异与疾病严重程度较高相关。这些发现为男性不成比例的疾病易感性机理提供了见识，并确定了抗雄激素药物可作为COVID-19的候选疗法。