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Background: Hypoxia is commonly existed in tumors and lead to cancer cell chemo/radio-resistance. It is well-recognized that tumor hypoxia is a major challenge for the treatment of various solid tumors. Hyperoside (quercetin-3-O-galactoside, Hy) possesses antioxidant effects and has been reported to protect against hypoxia/reoxygenation induced injury in cardiomyocytes. Therefore, Hy may be attractive compound applicable to hypoxia-related diseases.Purpose: This study was designed to determine the role of Hy in hypoxia-induced proliferation of non-small cell lung cancer cells and the underlying mechanism.Study Design and Methods: A549, a human non-small cell lung cancer (NSCLC) cell line, was used in the present study. 1% O2 was used to mimic the in vivo hypoxic condition of NSCLC. The potential mechanisms of Hy on hypoxia-induced A549 survival and proliferation, as well as the involvement of AMPK/HO-1 pathway were studied via CCK-8 assay, EdU staining, flow cytometry, qRT-PCR and western blot.Results: We showed that pretreatment with Hy suppressed hypoxia-induced A549 survival and proliferation in dose-dependent manner. In terms of mechanism, hypoxia-treated A549 showed the lower AMPK phosphorylation and the reduced HO-1 expression, which were reversed by Hy pretreatment. Both AMPK inhibitor (Compound C) and HO-1 activity inhibitor (Zinc protoporphyrin IX) abolished Hy-evoked A549 cell death under hypoxia stimuli. Of note, Ferrous iron contributed to Hy-induced A549 cell death under hypoxia, while Hy had no effect on lipid peroxidation under hypoxia.Conclusion: Taken together, our results highlighted the beneficial role of Hy against hypoxia-induced A549 survival and proliferation through ferrous accumulation via AMPK/HO-1 axis. [ABSTRACT FROM AUTHOR]