@article{APS11518,
author = {Xiao-jun Zhao and Yang Xu and Cong-hui Zhang and Cong Zhao and Li Liu and Xiao-wei Wang and Meng-yan Wang and Zi-xiang Gao and Rong-guang Shao and Li-qiang Qi and Yong-sheng Che and Wu-li Zhao},
title = {Secoemestrin C exerts rapid and prominent anti-breast cancer effect in triple-negative breast cancer by inducing SLX4 and YAP degradation},
journal = {Acta Pharmacologica Sinica},
volume = {14},
number = {5},
year = {2026},
keywords = {},
abstract = {Mitochondrial DNA (mtDNA) mutations are the most common cause in aberrant mitochondrion-leading cancer, exploration of direct targeting mutated mtDNA still remains incomplete. Secoemestrin C (Sec C) is epitetrathiodioxopiperazine derived from the endophytic fungus, which exhibited a rapid and prominent anti-breast cancer effect in triple-negative breast cancer (TNBC). In this study we investigated the anticancer mechanism of Sec C, especially its effect on TNBC cells. We showed that Sec C potently inhibited the viability of both TNBC (MDA-MB-231, HS578T, BT-549) and non-TNBC (MCF-7, T47D, SK-BR-3) cells in vitro with IC50 values of 1−2 μM. In MDA-MB-231 cells, treatment with Sec C (2 μM) induced DNA breakage and subsequent apoptosis. Furthermore, treatment with Sec C (2 μM) caused mtDNA damage, mitochondrial ubiquitination and subsequent mitophagy in MDA-MB-231 and MCF-7 cells. RNA-seq analysis revealed that Sec C mitigated YAP level in time and dose-dependent manner either in MDA-MB-231 and MCF-7 cells. By re-analyzing the Sec C-responsive gene network proteins, we identified SLX4 as an oncogene promoting breast cancer development, potentially by stabilizing mtDNA to suppress pathologic mitochondrion mitophagy. Specifically, Sec C initiated MDA-MB-231 cells to yield ROS that induced SLX4 ubiquitination and degradation, leading to mtDNA damage and exacerbated mitophagy and promoted YAP degradation bypassing YAP-driven DNA repair pathways. This study not only demonstrates that Sec C is a rapid and prominent anti-breast cancer drug for TNBC, but also reveals SLX4 as a novel mtDNA stabilizer supporting breast cancer progression, positioning it as both a prognostic biomarker and therapeutic target.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/11518}
}