Hepatocellular carcinoma (HCC), which accounts for approximately 90% of primary liver cancer, is commonly treated with surgical resection. However, most patients lose the opportunity to receive this therapeutic strategy due to delayed diagnosis and rapid tumor progression. Long noncoding RNAs (lncRNAs) have been demonstrated to play essential roles in the initiation and progression of HCC. However, the function of the novel lncRNA neuropeptide S receptor 1 antisense RNA 1 (NPSR1-AS1) in HCC and its potential mechanism, is unclear. Here, our microarray data revealed NPSR1-AS1 as a novel hypoxia-responsive lncRNA in HCC cells. Interestingly, hypoxia-inducible factor-1 alpha (HIF-1 alpha) knockdown abolished hypoxia-induced NPSR1-AS1 expression in HCC cells. NPSR1-AS1 expression was upregulated in HCC tissues and cell lines. Next, the ectopic expression of NPSR1-AS1 facilitated the proliferation and glycolysis of HCC cells. In contrast, NPSR1-AS1 silencing repressed HCC cell proliferation and glycolysis. Mechanistically, NPSR1-AS1 overexpression increased the levels of p-ERK1/2 and pyruvate kinase M2 (PKM2) in HCC cells. NPSR1-AS1 knockdown abrogated hypoxia-induced the activation of the MAPK/ERK pathway in HCC cells. Importantly, NPSR1-AS1 depletion partially reversed hypoxia-induced proliferation and glycolysis of HCC cells in vitro. In conclusion, hypoxia-inducible NPSR1-AS1 promotes the proliferation and glycolysis of HCC cells, possibly by regulating the MAPK/ERK pathway, suggesting an underlying therapeutic strategy for HCC. (C) 2020 Elsevier Inc. All rights reserved.