Regorafenib (RGF) is a critical second-line therapy for advanced hepatocellular carcinoma (HCC) following disease progression on sorafenib; however, the rapid onset of RGF resistance poses a significant barrier to enhancing patient outcomes. In this study, CRISPR/Cas9 screening in RGF-treated HCC cells identified Zinc Finger Protein 207 (ZNF207) as a primary driver of resistance. Further analysis revealed that ZNF207 promotes resistance by inducing antioxidant responses that inhibit ferroptosis, a form of iron-dependent cell death. Mechanistically, ZNF207 facilitates the lactylation of peroxiredoxin 1 (PRDX1) at lysine 67, enhancing nuclear translocation and activation of nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of antioxidant pathways. This ZNF207-PRDX1-NRF2 pathway creates a ferroptosis-resistant, pro-survival environment under RGF treatment, enabling HCC cells to evade cell death. Functional assays demonstrated that ZNF207 knockdown significantly enhances RGF sensitivity by restoring ferroptosis, with additional findings showing that disrupting PRDX1 lactylation or NRF2 activity similarly reverses resistance. Together, these findings establish a critical link between protein lactylation and RGF resistance, positioning the ZNF207-PRDX1-NRF2 axis as a promising therapeutic target to enhance treatment efficacy in HCC. The implications of this research extend beyond HCC, indicating that targeting ferroptosis-suppressive pathways may offer a broader approach to overcoming resistance in various cancers.