RAC1 directly phosphorylates both PKM2 and FBP1 to promote radioresistance in hepatocellular carcinoma

  • Mol Ther. 2025 Nov 7:S1525-0016(25)00870-6. doi: 10.1016/j.ymthe.2025.10.049.
Yabo Jiang  1 ,  Kaixiao Zhou  2 ,  Xubiao Wei  1 ,  Jinkai Feng  3 ,  Bin Zhou  1 ,  Chang Liu  1 ,  Juxian Sun  1 ,  Hongfei Zhu  1 ,  Zonghan Liu  1 ,  Nan Yuan  2 ,  Yecheng Li  4 ,  Xuanyu Meng  2 ,  Jianping Cao  5 ,  Yang Jiao  6 ,  Shuqun Cheng  7
Affiliations
  • 1. Sixth Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Military Medical University, 225 Changhai Road, Shanghai 200438, China.
  • 2. State Key Laboratory of Radiology and Radiation Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, 199 Renai Road, Suzhou, Jiangsu Province 215123, China.
  • 3. Sixth Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Military Medical University, 225 Changhai Road, Shanghai 200438, China; Department of Hepatobiliary Surgery, No. 971 Hospital of Chinese PLA Navy, Qingdao 266071, China.
  • 4. Department of General Surgery, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province 215004, China.
  • 5. State Key Laboratory of Radiology and Radiation Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, 199 Renai Road, Suzhou, Jiangsu Province 215123, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Radiology and Radiation Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, 199 Renai Road, Suzhou, Jiangsu Province 215123, China. Electronic address: [email protected].
  • 7. Sixth Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Military Medical University, 225 Changhai Road, Shanghai 200438, China. Electronic address: [email protected].
PMID: 41204670 DOI: 10.1016/j.ymthe.2025.10.049
Abstract

Radiotherapy (RT) is a promising treatment for hepatocellular carcinoma (HCC), but resistance limits its efficacy. This study reveals that Rac family small GTPase 1 (RAC1) is overexpressed in radioresistant HCC patients and promotes resistance by directly phosphorylating Pyruvate Kinase M2 (PKM2) and fructose-1,6-bisphosphatase 1 (FBP1), leading to enhanced glycolytic flux. Introducing mutations in PKM2 (S172A) and FBP1 (T309A) effectively inhibits tumor growth. Additionally, combining RT with the US Food and Drug Administration-approved drug foscarnet sodium, which inhibits RAC1 activity, significantly improves therapeutic outcomes in vivo. These findings identify RAC1 as a key regulator of radioresistance and a potential therapeutic target in HCC.

Keywords
FBP1; PKM2; RAC1; glycolysis; hepatocellular carcinoma; phosphorylation; radiotherapy resistance.
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