Molecular mechanism study reveals that high CFL1 expression could enhance the nuclear translocation of Nrf2 via impairing the Keap1–Nrf2 interaction to promote PHGDH transcription and thus improve serine synthesis and metabolism, which could accelerate the production of antioxidants (i.e., NADH and NADPH) to scavenge the excessive ROS triggered by sorafenib, ultimately leading to the weakened sorafenib sensitivity of HCC cells. This evidence concerns the gene KEAP1 and hepatocellular carcinoma.