三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌，目前尚无有效的治疗方法。在本研究中，我们报道了一种天然产物ER跨膜蛋白转运抑制剂Ipomoeassin F对TNBC细胞生长的选择性抑制作用。通过蛋白组学分析发现，Ipomoeassin F显著降低了TNBC细胞中ER分子伴侣蛋白（包括PDIA6和PDIA4）的水平，并诱导了ER应激、未折叠蛋白应激（UPR）和自噬。在机制上，作为Sec61α含有的ER跨膜蛋白转运抑制剂，Ipomoeassin F阻断了PDIA6的ER转运，并诱导其经蛋白酶体降解。通过RNA干扰技术沉默PDIA6或PDIA4，或使用蛋白二硫酰异构酶的小分子抑制剂处理TNBC细胞，成功重现了Ipomoeassin F的表型，包括诱导ER应激、UPR和自噬，说明减少PDIAs是Ipomoeassin F药物效应的关键介导因子。此外，Ipomoeassin F在小鼠肿瘤异种移植模型中显著抑制了TNBC的生长，并导致肿瘤样本中PDIA6和PDIA4水平明显降低。我们的研究表明，Sec61α含有的ER跨膜蛋白转运抑制剂和PDIAs是TNBC的潜在药物靶点，并暗示Ipomoeassin F可能成为开发针对ER转运靶向治疗TNBC的先导化合物。©作者。

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer where no effective therapy has been developed. Here, we report that the natural product ER translocon inhibitor ipomoeassin F is a selective inhibitor of TNBC cell growth. A proteomic analysis of TNBC cells revealed that ipomoeassin F significantly reduced the levels of ER molecular chaperones, including PDIA6 and PDIA4, and induced ER stress, unfolded protein response (UPR) and autophagy in TNBC cells. Mechanistically, ipomoeassin F, as an inhibitor of Sec61α-containing ER translocon, blocks ER translocation of PDIA6, inducing its proteasomal degradation. Silencing of PDIA6 or PDIA4 by RNA interferences or treatment with a small molecule inhibitor of the protein disulfide isomerases in TNBC cells successfully recapitulated the ipomoeassin F phenotypes, including the induction of ER stress, UPR and autophagy, suggesting that the reduction of PDIAs is the key mediator of the pharmacological effects of ipomoeassin F. Moreover, ipomoeassin F significantly suppressed TNBC growth in a mouse tumor xenograft model, with a marked reduction in PDIA6 and PDIA4 levels in the tumor samples. Our study demonstrates that Sec61α-containing ER translocon and PDIAs are potential drug targets for TNBC and suggests that ipomoeassin F could serve as a lead for developing ER translocon-targeted therapy for TNBC.© The author(s).