Molecular mechanism study indicated that CFL1 could impair the interaction between Kelch‐like ECH‐associated protein 1 (Keap1) and erythroid 2‐related factor 2 (Nrf2) via promoting the depolymerization of filamentous actin (F‐actin) into globular actin (G‐actin) and improve the nuclear translocation of Nrf2 to enhance the transcription of phosphoglycerate dehydrogenase (PHGDH), which could accelerate the production of antioxidants via enhancing serine synthesis and metabolism to scavenge the excessive ROS triggered by sorafenib, thereby impairing the sensitivity of HCC cells to sorafenib. Here, PHGDH is linked to hepatocellular carcinoma.