Yang Tianfeng, Zhang Suyu, Nie Kun, Cheng Cheng, Peng Xiuhong, Huo Jian, Zhang Yanmin
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an 710061, PR China.
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an 710061, PR China.
Drug Resist Updat. 2025 Sep;82:101274. doi: 10.1016/j.drup.2025.101274. Epub 2025 Jul 12.
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.
瑞戈非尼（RGF）是索拉非尼治疗后疾病进展的晚期肝细胞癌（HCC）的关键二线治疗药物；然而，RGF耐药性的迅速出现对改善患者预后构成了重大障碍。在本研究中，对接受RGF治疗的HCC细胞进行CRISPR/Cas9筛选，确定锌指蛋白207（ZNF207）是耐药的主要驱动因素。进一步分析表明，ZNF207通过诱导抑制铁死亡（一种铁依赖性细胞死亡形式）的抗氧化反应来促进耐药。从机制上讲，ZNF207促进过氧化物酶1（PRDX1）在赖氨酸67处的乳酰化，增强核因子红细胞2相关因子2（NRF2）的核转位和激活，NRF2是抗氧化途径的主要调节因子。这种ZNF207-PRDX1-NRF2途径在RGF治疗下创造了一个抗铁死亡的促生存环境，使HCC细胞能够逃避细胞死亡。功能试验表明，敲低ZNF207可通过恢复铁死亡显著增强RGF敏感性，其他研究结果表明，破坏PRDX1乳酰化或NRF2活性同样可逆转耐药。总之，这些发现建立了蛋白质乳酰化与RGF耐药之间的关键联系，将ZNF207-PRDX1-NRF2轴定位为增强HCC治疗疗效的有前景的治疗靶点。这项研究的意义不仅限于HCC，表明靶向抑制铁死亡的途径可能为克服各种癌症的耐药性提供更广泛的方法。
