三阴性乳腺癌（TNBC）是一种具有高侵袭性、转移潜能和预后差的侵袭性乳腺癌亚型。上皮间质转化（EMT）在TNBC进展中起着关键作用，成为TNBC治疗的有希望的靶点。本研究评估了一种新型合成双分割素衍生物N-3，它抑制了MDA-MB-231和4T1 TNBC细胞的EMT相关迁移和侵袭。结果与FOXC1表达和转录活性的抑制一致。附加研究表明，N-3通过增强泛素化和降解来降低FOXC1的蛋白稳定性。此外，N-3降低了p-p38的表达和FOXC1的相互作用，降低了p38调节的FOXC1的稳定性。进一步，N-3在体内模拟的肺转移模型中阻断了TNBC的转移，与FOXC1的抑制和EMT有关。这些结果突出了N-3作为TNBC转移治疗的潜力。因此，FOXC1调控可能成为TNBC转移的一种新的靶向治疗策略。版权所有 © 2023 Elsevier Inc. 发布。

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high invasiveness, metastatic potential, and poor prognosis. Epithelial-mesenchymal transition (EMT) is pivotal in TNBC progression, becoming a promising target for TNBC treatment. Our study evaluated N-3, a novel synthetic bifendate derivative, which inhibited the EMT-associated migration and invasion of MDA-MB-231 and 4T1 TNBC cells. The results were consistent with the suppression of FOXC1 expression and transcriptional activity. Additional studies indicated that N-3 reduced the protein stability of FOXC1 by enhancing ubiquitination and degradation. Moreover, N-3 downregulated p-p38 expression and FOXC1 interaction, decreasing the stability of p38-regulated FOXC1. Further, N-3 blocked TNBC metastasis with an artificial lung metastasis model in vivo, related to FOXC1 suppression and EMT. These results highlight the potential of N-3 as a TNBC metastasis treatment. Therefore, FOXC1 regulation could be a novel targeted therapeutic strategy for TNBC metastasis.Copyright © 2023. Published by Elsevier Inc.