Based on genome-wide RNA-seq analysis, which identified mitochondrial oxidative phosphorylation (OxPhos) and Hmox1 upregulation as potential pro-survival mechanisms in sorafenib-resistant cells, we investigated whether SR9009, a synthetic agonist of the nuclear receptor REV-ERBα/β, heme competitor, and inhibitor of mitochondrial respiration, could enhance the antitumor efficacy of sorafenib in liver cancer models. This evidence concerns the gene HMOX1 and liver cancer.