Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third leading cause of cancer-related death worldwide. Sorafenib is one of the most widely used first-line treatments for HCC, but patients generally develop sorafenib resistance within a few months, and the cause is not yet clear. Researchers recently investigated the possible role of PAK1, an enzyme associated with drug resistance in other cancers. They found that PAK1 was highly expressed in human HCC tissues and that higher PAK1 expression was associated with lower patient survival. In vitro, PAK1 promoted HCC cell proliferation and malignant characteristics and activation of PAK1 increased the amount of sorafenib required to kill cancer cells, indicating that it induced drug resistance. Treating HCC with all-trans retinoic acid (ATRA), a vitamin A metabolite that’s beneficial in several cancers, helped restore sorafenib’s efficacy. Specifically, ATRA downregulated PAK1 to inhibit HCC progression and increase cancer cells’ sensitivity to sorafenib both in vitro and in mice. Although more research is needed, the findings reveal the role of PAK1 in HCC progression and sorafenib resistance and suggest that combination of sorafenib and ATRA or other PAK1 inhibitors will provide more effective treatment options for HCC.