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Objective: Intratumoral hypoxia is an essential feature of hepatocellular carcinoma (HCC). Herein, we investigated the hypoxia-based heterogeneity and relevant clinical implication in HCC. Methods: Three HCC cohorts: TCGA-LIHC, LICA-FR, and LIRI-JP were retrospectively gathered. Consensus clustering analysis was utilized for hypoxia-based classification based upon transcriptome of hypoxia genes. Through LASSO algorithm, a hypoxia-relevant prognostic signature was built. Immunotherapeutic response was inferred through analyzing immune checkpoints, T cell inflamed score, TIDE score, and TMB score. RNF145 expression was measured in normoxic or hypoxic HCC cells. In RNF145-knockout cells, CCK-8, TUNEL, and scratch tests were implemented. Results: HCC patients were classified into two hypoxia subtypes, with more advanced stages and poorer prognosis in cluster2 than cluster1. The heterogeneity in tumor infiltrating immune cells and genetic mutation was found between subtypes. The hypoxia-relevant prognostic model was proposed, composed of ANLN, CBX2, DLGAP5, FBLN2, FTCD, HMOX1, IGLV1-44, IL33, LCAT, LPCAT1, MKI67, PFN2, RNF145, S100A9, and SPP1). It was predicted that high-risk patients presented worse prognosis with an independent and reliable manner. Based upon high expression of immune checkpoints (CD209, CTLA4, HAVCR2, SIRPA, TNFRSF18, TNFRSF4, and TNFRSF9), high T cell inflamed score, low TIDE score and high TMB score, high-risk patients might respond to immunotherapy. Experimental validation showed that RNF145 was upregulated in hypoxic HCC cells, RNF145 knockdown attenuated proliferation and migration, but aggravated apoptosis in HCC cells. Conclusion: Altogether, the hypoxia-based classification and prognostic signature might be useful for prognostication and guiding treatment of HCC. [ABSTRACT FROM AUTHOR]