Curaxin CBL0137旨在同时调节p53和核因子-κB，并通过抑制多种癌细胞的增殖和诱导细胞凋亡发挥抗肿瘤活性。然而，CBL0137能否诱导火凋亡尚未报告。本研究表明，CBL0137通过活性氧（ROS）/BAX途径诱导caspase-3 / gasdermin E（GSDME）依赖的火凋亡。在卵巢癌细胞中，CBL0137失活了可以促进染色质转录的染色质重塑复合物，导致抗氧化基因转录减少和氧化作用增加，从而增加ROS水平。ROS通过线粒体ROS招募BAX到线粒体膜上，并诱导细胞色素C的释放来切割caspase-3。这导致GSDME的N端裂解在细胞膜上形成孔并诱导火凋亡。体内实验结果表明，CBL0137在卵巢癌细胞中也具有抗肿瘤作用。我们的研究结果揭示了CBL0137诱导卵巢癌细胞火凋亡的机制和靶点，并表明CBL0137是一种有前途的卵巢癌治疗药物。版权所有©2023年作者。由Elsevier Masson SAS发表。保留所有权利。

Curaxin CBL0137 was designed to regulate p53 and nuclear factor-κB simultaneously and exhibits antitumor activity by inhibiting tumor cell proliferation and inducing apoptosis in multiple cancers. However, whether CBL0137 can induce pyroptosis has not yet been reported. This study demonstrated that CBL0137 induces caspase-3/gasdermin E (GSDME)-dependent pyroptosis via the reactive oxygen species (ROS)/BAX pathway. In ovarian cancer cells, CBL0137 inactivated the chromatin remodeling complex which could facilitate chromatin transcription, leading to the decreased transcription of antioxidant genes and oxidation and causing increased ROS levels. BAX was recruited on the mitochondrial membrane by mitochondrial ROS and induced the release of cytochrome c to cleave caspase-3. This led to the cleavage of the N-terminal of GSDME to form pores on the cell membrane and induced pyroptosis. Results of in vivo experiments revealed that CBL0137 also had anti-tumor effects on ovarian cancer cells in vivo. Our study outcomes reveal the mechanisms and targets of CBL0137 inducing pyroptosis in ovarian cancer cells and indicate that CBL0137 is a promising therapeutic agent for ovarian cancer.Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.