子宫肌瘤是女性子宫肌层中最常见的良性肿瘤，其特征为异常的细胞外基质沉积和子宫平滑肌细胞恶性增生，复发率较高。本研究探讨了海洋天然产物曼扎敏A（Manz A）作为治疗子宫肌瘤的潜力。Manz A在体外和体内抑制了平滑肌瘤细胞的增殖，通过阻断细胞周期进展和诱导caspase介导的凋亡。我们进行了靶点预测分析，并确定了甾醇O-酰转移酶（SOATs）作为Manz A的潜在靶点。Manz A减少了胆固醇酯化和脂滴形成，与SOAT表达的降低一致。作为SOAT的下游靶点，Manz A通过抑制β-连环蛋白/纤维连接蛋白/金属蛋白酶轴，阻止了细胞外基质沉积，并增强了自噬的周转。SOAT抑制导致过度的游离脂肪酸积累，进而通过PERK/eIF2α/CHOP信号通路，引发线粒体氧化磷酸化的活性氧应激和内质网应激。Manz A对细胞增殖的抑制作用部分恢复于PERK敲除，并被牛磺胆酸消除，提示氧化应激在Manz A的作用机制中起着关键作用。这些发现表明，通过抑制SOATs靶向治疗子宫肌瘤可能是一种有前景的治疗方法。版权所有©2023作者。由Elsevier B.V.出版公司发表，版权所有。

Uterine fibroids, the most common benign tumors of the myometrium in women, are characterized by abnormal extracellular matrix deposition and uterine smooth muscle cell neoplasia, with high recurrence rates. Here, we investigated the potential of the marine natural product manzamine A (Manz A), which has potent anti-cancer effects, as a treatment for uterine fibroids. Manz A inhibited leiomyoma cell proliferation in vitro and in vivo by arresting cell cycle progression and inducing caspase-mediated apoptosis. We performed target prediction analysis and identified sterol o-acyltransferases (SOATs) as potential targets of Manz A. Cholesterol esterification and lipid droplet formation were reduced by Manz A, in line with reduced SOAT expression. As a downstream target of SOAT, Manz A also prevented extracellular matrix deposition by inhibiting the β-catenin/fibronectin/metalloproteinases axis and enhanced autophagy turnover. Excessive free fatty acid accumulation by SOAT inhibition led to reactive oxygen species to impair mitochondrial oxidative phosphorylation and trigger endoplasmic reticulum stress via PERK/eIF2α/CHOP signaling. The inhibitory effect of ManzA on cell proliferation was partially restored by PERK knockdown and eliminated by tauroursodeoxycholic acid, suggesting oxidative stress plays a critical role in the mechanism of action of Manz A. These findings suggest that targeting SOATs by Manz A may be a promising therapeutic approach for uterine fibroids.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.