Here, we (1) show that OSM induces the expression of HIF-1 α in several HCC cell lines and immortalized hepatocytes, (2) demonstrate that OSM stimulation leads to a hypoxia-like metabolic phenotype in three clones of the immortalized hepatocyte cell line PH5CH, (3) provide evidence that HIF-1 α-mediated PDK1 upregulation is necessary to induce OSM-dependent metabolic reprogramming in PH5CH cells, and (4) show that OSM-dependent HIF-1 α upregulation is not sufficient to induce metabolic reprogramming in the HCC cell lines HepG2 and JHH-4. Here, SETD2 is linked to hepatocellular carcinoma.