This study focused on determining the anticancer effect of paeoniflorin and geniposide mixture (PFGS) combined with sorafenib (Sor) in hepatocellular carcinoma (HCC) and, in particular, whether PFGS increases the antitumor effect of Sor by modulating the NF-κB/HIF-2α/SerpinB3 pathway. The gene discussed is SERPINB3; the disease is hepatocellular carcinoma.