乳腺癌是女性最常见的恶性肿瘤之一，具有高致死率和不良预后。迫切需要发现乳腺癌转移的新治疗靶点。在这里，我们通过免疫组织化学方法发现，乳腺癌患者原发肿瘤中载脂蛋白C1（APOC1）表达上调，并且与复发和转移紧密相关。Kaplan-Meier Plotter数据库显示，乳腺癌患者中高水平的APOC1与更差的总生存期（OS）和无复发生存期（RFS）密切相关。在机制上，APOC1沉默显著抑制了MAPK/ERK激酶通路，并限制了NF-κB，从而在体外下调与生长和转移相关的靶基因的转录。基于这一调控机制，我们将这些发现开发成潜在的治疗药物，使用谷胱甘肽（GSH）响应性纳米粒子（NPs）进行全身APOC1小分子干扰RNA传递，NPs（siAPOC1）沉默了APOC1表达，并在体内的原位和肝转移模型中产生了积极的抗肿瘤效果。综上所述，GSH响应性NP介导的siAPOC1传递被证明在多种肿瘤模型中调控生长和转移具有有效性。这些发现表明APOC1可能是预测乳腺癌患者预后的潜在生物标志物，而NP介导的APOC1沉默可能是探索乳腺癌转移新治疗策略的新方法。© 2023. Science China Press.

Breast cancer is one of the most common malignant tumors with high mortality and poor prognosis in women. There is an urgent need to discover new therapeutic targets for breast cancer metastasis. Herein, we identified that Apolipoprotein C1 (APOC1) was up-regulated in primary tumor of breast cancer patient that recurrence and metastasis by immunohistochemistry (IHC). Kaplan-Meier Plotter database showed that high levels of APOC1 in breast cancer patients were strongly associated with worse overall survival (OS) and relapse-free survival (RFS). Mechanistically, APOC1 silencing significantly inhibits MAPK/ERK kinase pathway and restrains the NF-κB to decrease the transcription of target genes related to growth and metastasis in vitro. Based on this regulatory mechanism, we developed these findings into potential therapeutic drugs, glutathione (GSH) responsive nano-particles (NPs) were used for systemic APOC1 siRNA delivery, NPs (siAPOC1) silenced APOC1 expression, and subsequently resulted in positive anti-tumor effects in orthotopic and liver metastasis models in vivo. Taken together, GSH responsive NP-mediated siAPOC1 delivery was proved to be effective in regulating growth and metastasis in multiple tumor models. These findings show that APOC1 could be a potential biomarker to predict the prognosis of breast cancer patients and NP-mediated APOC1 silencing could be new strategies for exploration of new treatments for breast cancer metastasis.© 2023. Science China Press.