Our study first demonstrates that CFL1 could impair the Keap1–Nrf2 interaction via promoting the depolymerization of F‐actin into G‐actin and improve the nuclear translocation of Nrf2 to enhance PHGDH transcription and promote serine synthesis and metabolism, which could induce the production of more antioxidants to scavenge the excessive ROS triggered by sorafenib and thus impair sorafenib sensitivity of HCC cells. The gene discussed is PHGDH; the disease is hepatocellular carcinoma.