Metastasis to the lungs is a leading cause of death for breast cancer patients. Therefore, effective therapies are urgently needed to prevent and treat breast cancer lung metastasis In this study, we uncovered a mechanism by which NAD(P)H:quinone oxidoreductase 1 (NQO1) orchestrates lung metastasis. NQO1 stabilized and upregulated peptidyl-prolyl cis-trans isomerase A (PPIA), a chaperone that regulates protein conformation and activity, by preventing its oxidation at a critical cysteine residue C161. PPIA subsequently activated CD147, a membrane protein that facilitates cell invasion. Moreover, NQO1-induced secretion of PPIA modulated the immune landscape of both primary and lung metastatic sites. Secreted PPIA engaged CD147 on neutrophils and triggered the release of neutrophil extracellular traps (NET) and neutrophil elastase, which enhanced tumor progression, invasiveness and lung colonization. Pharmacological targeting of PPIA effectively inhibited NQO1-mediated breast cancer lung metastasis. These findings reveal a previously unrecognized NQO1-PPIA-CD147-NET axis that drives breast cancer lung metastasis. Inhibiting this axis is a potential therapeutic strategy to limit lung metastasis in breast cancer patients.

中文翻译：

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NQO1 触发中性粒细胞募集和 NET 形成以驱动浸润性乳腺癌的肺转移


肺部转移是乳腺癌患者死亡的主要原因。因此，迫切需要有效的疗法来预防和治疗乳腺癌肺转移 在这项研究中，我们揭示了 NAD（P）H：醌氧化还原酶 1 （NQO1） 协调肺转移的机制。NQO1 通过阻止其在关键半胱氨酸残基 C161 处氧化，稳定和上调肽基-脯氨酰顺反异构酶 A （PPIA），PPIA 是一种调节蛋白质构象和活性的伴侣。PPIA 随后激活了 CD147，这是一种促进细胞侵袭的膜蛋白。此外，NQO1 诱导的 PPIA 分泌调节原发性和肺转移部位的免疫景观。分泌的 PPIA 与中性粒细胞上的 CD147 结合并触发中性粒细胞胞外陷阱 （NET） 和中性粒细胞弹性蛋白酶的释放，从而增强肿瘤进展、侵袭性和肺定植。PPIA 的药理学靶向有效抑制了 NQO1 介导的乳腺癌肺转移。这些发现揭示了以前未识别的 NQO1-PPIA-CD147-NET 轴，该轴驱动乳腺癌肺转移。抑制该轴是限制乳腺癌患者肺转移的潜在治疗策略。