2. Academic Validation
  3. RAC1 directly phosphorylates both PKM2 and FBP1 to promote radioresistance in hepatocellular carcinoma

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

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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