Our results collectively indicated that HIF-1α could directly bind to the promoter to activate MAPKAPK5-AS1 transcription, and MAPKAPK5-AS1 regulated HIF-1α expression through PLAGL2 form a hypoxia-mediated MAPKAPK5-AS1/PLAGL2/HIF-1α signaling loop in HCC. The gene discussed is HIF1A; the disease is hepatocellular carcinoma.