Taken together, the present study showed that GHR knockdown enhanced the sensitivity of HCC cells to sorafenib, and the inactivation of PI3K/AKT/ERK1/2 signaling pathways might be the underlying mechanisms, highlighting the absence of GHR as a promising way to enhance sorafenib efficacy in HCC. The gene discussed is MAPK3; the disease is hepatocellular carcinoma.