胆固醇代谢对于多种癌症的进展至关重要，而胆固醇如何影响肺（一种低胆固醇组织）以促进癌症转移及其潜在机制仍不清楚。在这项研究中，我们发现转移性肺腺癌细胞通过内源性胆固醇生物合成获得细胞脱氢胆固醇和胆固醇，而不是通过胆固醇治疗摄取。此外，我们证明外源性胆固醇可作为信号分子通过 GLI2 诱导 FOXA3（脂质代谢的关键转录因子）。随后，ChIP-seq 分析和分子研究表明，FOXA3 转录激活 Hmgcs1（胆固醇生物合成的必需酶），诱导内源性脱氢胆固醇和胆固醇水平，从而导致膜组成变化和细胞迁移。相反，FOXA3 敲低或敲除可阻断小鼠体内的胆固醇生物合成和肺腺癌转移。此外，强效 FOXA3 抑制剂厚朴酚可抑制肺腺癌患者来源的类器官 (PDO) 中的转移基因程序。总而言之，我们的研究结果揭示了独特的胆固醇代谢和 FOXA3 对肺腺癌转移的贡献。版权所有：© 2024 Wang 等人。这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。

Cholesterol metabolism is vital for multiple cancer progression, while how cholesterol affects lung, a low-cholesterol tissue, for cancer metastasis and the underlying mechanism remain unclear. In this study, we found that metastatic lung adenocarcinoma cells acquire cellular dehydrocholesterol and cholesterol by endogenous cholesterol biosynthesis, instead of uptake upon cholesterol treatment. Besides, we demonstrated that exogenous cholesterol functions as signaling molecule to induce FOXA3, a key transcription factor for lipid metabolism via GLI2. Subsequently, ChIP-seq analysis and molecular studies revealed that FOXA3 transcriptionally activated Hmgcs1, an essential enzyme of cholesterol biosynthesis, to induce endogenous dehydrocholesterol and cholesterol level for membrane composition change and cell migration. Conversely, FOXA3 knockdown or knockout blocked cholesterol biosynthesis and lung adenocarcinoma metastasis in mice. In addition, the potent FOXA3 inhibitor magnolol suppressed metastatic gene programs in lung adenocarcinoma patient-derived organoids (PDOs). Altogether, our findings shed light onto unique cholesterol metabolism and FOXA3 contribution to lung adenocarcinoma metastasis.Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.