Studies have shown that hypoxia can induce cytoskeletal injury and remodeling through the activation of the RhoA/ROCK signaling pathway by hypoxia-inducible factor-1α (HIF-1α). Our previous study confirmed that CAPZA1 can modulate EMT by regulating actin cytoskeleton remodeling. However, the relationship between HIF-1α and CAPZA1 has not been illustrated. Therefore, this study aimed to investigate the mechanism by which hypoxia induces the remodeling of the actin cytoskeleton by regulating CAPZA1 in hepatocellular carcinoma (HCC) cells. In the present study, we showed that the low expression of CAPZA1 promotes HCC cell invasion and migration in vitro and in vivo by regulating actin cytoskeleton remodeling to drive EMT. Furthermore, we found that the combination of PIP2 and CAPZA1 enables CAPZA1 to be released from the barbed end of F-actin, which in turn drives the remodeling of the actin cytoskeleton. Finally, we confirmed that hypoxia increases PIP2 levels and its binding to CAPZA1 in HCC cells via the HIF-1α/RhoA/ROCK1 pathway. Thus, CAPZA1 and PIP2 could be therapeutic targets to inhibit the invasion and migration promoted by hypoxia in HCC cells. Copyright © 2019 Elsevier B.V. All rights reserved.