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Background <p>Radioresistance is an objective biological factor that affects the efficacy of clinical radiotherapy in hepatocellular carcinoma (HCC). However, the mechanism involved has not yet been fully understood.</p> Methods <p>Integrative analysis of HCC patient data with RNA-seq and IHC. Radiosensitivity assessed by colony formation assays using HCC cell lines and xenograft models established in B-NDG mice. USP11 promoter activity measured by dual luciferase reporter. Protein interactions analyzed by Co-IP/GST pulldown; post-translational modifications by ubiquitylation assays. Rac1 activity was quantified by measuring GTP-bound levels. Rac1 structural dynamics simulated through molecular dynamics. Functional validation performed using pharmacological inhibitors, genetic depletion and site-directed mutagenesis.</p> Results <p>Elevated activated Rac1(Rac1-GTP) predicted poor radiotherapeutic response. Ionizing radiation (IR) activated Rac1 and induced its nuclear translocation. Rac1-GTP is required for the transcriptional upregulation of USP11. USP11 stabilised Rac1-GTP via deubiquitination at residues K123/K147/K183, forming a self-reinforcing Rac1-USP11 amplification loop driving radioresistance. USP11 knockdown or mutation of Rac1 deubiquitination sites (K123/K147/K183) destabilized Rac1-GTP and reversed radioresistance. Elevated Rac1-GTP and USP11 correlated with adverse clinical outcomes. Critically, combined NSC23766/Mitoxantrone treatment showed enhanced radiosensitization.</p> Conclusion <p>This study identifies the Rac1-USP11 reciprocal feedback loop as a novel, self-reinforcing mechanism driving radioresistance in HCC. Targeting this loop via combined Rac1-GTP/USP11 inhibition represents a promising therapeutic strategy for radiosensitizing HCC.</p>

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The Rac1-USP11 feedback amplification loop: a radiation-activated engine driving radioresistance in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Kaixiao Zhou,
  • Yabo Jiang,
  • Jiahao Guo,
  • Haobo Zhang,
  • Yuhao Hu,
  • Xuanyu Meng,
  • Yecheng Li,
  • Shaohua Wei,
  • Jian Wang,
  • Xubiao Wei,
  • Shuqun Cheng,
  • Jianping Cao,
  • Yang Jiao

摘要

Background

Radioresistance is an objective biological factor that affects the efficacy of clinical radiotherapy in hepatocellular carcinoma (HCC). However, the mechanism involved has not yet been fully understood.

Methods

Integrative analysis of HCC patient data with RNA-seq and IHC. Radiosensitivity assessed by colony formation assays using HCC cell lines and xenograft models established in B-NDG mice. USP11 promoter activity measured by dual luciferase reporter. Protein interactions analyzed by Co-IP/GST pulldown; post-translational modifications by ubiquitylation assays. Rac1 activity was quantified by measuring GTP-bound levels. Rac1 structural dynamics simulated through molecular dynamics. Functional validation performed using pharmacological inhibitors, genetic depletion and site-directed mutagenesis.

Results

Elevated activated Rac1(Rac1-GTP) predicted poor radiotherapeutic response. Ionizing radiation (IR) activated Rac1 and induced its nuclear translocation. Rac1-GTP is required for the transcriptional upregulation of USP11. USP11 stabilised Rac1-GTP via deubiquitination at residues K123/K147/K183, forming a self-reinforcing Rac1-USP11 amplification loop driving radioresistance. USP11 knockdown or mutation of Rac1 deubiquitination sites (K123/K147/K183) destabilized Rac1-GTP and reversed radioresistance. Elevated Rac1-GTP and USP11 correlated with adverse clinical outcomes. Critically, combined NSC23766/Mitoxantrone treatment showed enhanced radiosensitization.

Conclusion

This study identifies the Rac1-USP11 reciprocal feedback loop as a novel, self-reinforcing mechanism driving radioresistance in HCC. Targeting this loop via combined Rac1-GTP/USP11 inhibition represents a promising therapeutic strategy for radiosensitizing HCC.