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Hypoxia-inducible factor 1 (HIF-1) has been associated with distant tumor metastasis ; how ever, its function in the complex and multiple metastatic processes have not been fully elucidated yet.In the present study, we demonstrated that metastatic cancer cells transiently upregulated HIF-1 activity dur ing their metastatic colonization after extravasation in lungs in hypoxia-independent and reactive oxygen species-dependent manners.The transient activation induced the expression of lactate dehydrogenase A (LDHA) and phosphorylation of E1 a subunit of pyruvate dehydrogenase (PDH-E1 a), indicating the re programming of glucose metabolic pathways from mitochondrial oxidative phosphorylation to anaerobic gly colysis and lactic acid fermentation.Administration of a HIF-1 inhibitor, YC-1, inhibited the reprogram ming, increased intratumoral level of reactive oxygen species (ROS), and eventually suppressed the for mation of metastatic lung tumors.Taken together, these results indicate that HIF-l-mediated metabolic re programming is responsible for survival of metastatic cancer cells during their colonization in lungs by re ducing the level of cytotoxic and reactive species; and therefore, its blockade by HIF-1-inhibitors is a ra tional strategy to prevent tumor metastasis.This study was supported by973 key project (No :2011 CB503704), International Science & Technol ogy Cooperation Project of China and Japan (No: 2010DFA31900) ,the Research Fund of National Natu ral Science Foundation of China (No.30700653, 30901215, 60971055, 81102091,81172636), and by the Research Fund of Shaanxi Province Natural Science Foundation of China (No.2012K17-02-10).