子宫平滑肌肉肉瘤（ULMS）是一种恶性间质肿瘤，来源于子宫肌层，具有不良预后，并且目前的化疗反应极其有限。本研究旨在通过使用由1271个美国食品和药物管理局批准的药物组成的化学库进行三步筛选过程，寻找ULMS的新靶点。首先，我们评估了它们对ULMS细胞的抑制作用，并确定了四个候选药物：proscillaridin A、lanatoside C、氟脱氧尿嘧啶和地高辛。然后，我们将SK-UT-1细胞皮下或原位移植到小鼠中，建立了小鼠模型。体内分析表明，proscillaridin A和lanatoside C具有卓越的抗肿瘤作用。mRNA测序结果表明，在sirtuin信号通路中，解偶联蛋白2（UCP2）被抑制，增加了反应性氧化物（ROS），诱导细胞死亡。此外，UCP2的下调诱导ROS并抑制ULMS细胞生长。此外，对临床样本的分析表明，UCP2表达在RNA和蛋白水平上均显著上调，与子宫肌瘤组织相比。这些发现提示UCP2是一个潜在的治疗靶点，可以为ULMS患者的治疗策略的开发做出贡献。版权所有2023年作者。由Elsevier Ltd. 出版。保留所有权利。

Uterine leiomyosarcoma (ULMS) is a malignant stromal tumor arising from the myometrium with a poor prognosis and very limited response to current chemotherapy. This study aimed to identify novel targets for ULMS through a three-step screening process using a chemical library consisting of 1271 Food and Drug Administration-approved drugs. First, we evaluated their inhibitory effects on ULMS cells and identified four candidates: proscillaridin A, lanatoside C, floxuridine, and digoxin. Then, we subcutaneously or orthotopically transplanted SK-UT-1 cells into mice to establish mouse models. In vivo analyses showed that proscillaridin A and lanatoside C exerted a superior antitumor effect. The results of mRNA sequencing showed that uncoupling protein 2 (UCP2) was suppressed in the sirtuin signaling pathway, increasing reactive oxygen species (ROS) and inducing cell death. Moreover, the downregulation of UCP2 induced ROS and suppressed ULMS cell growth. Furthermore, analyses using clinical samples showed that UCP2 expression was significantly upregulated in ULMS tissues than in myoma tissues both at the RNA and protein levels. These findings suggested that UCP2 is a potential therapeutic target and can contribute to the development of novel therapeutic strategies in patients with ULMS.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.