RAC1 directly phosphorylates both PKM2 and FBP1 to promote radioresistance in hepatocellular carcinoma
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.
Authors
- Jianping Cao (ORCID: https://orcid.org/0000-0003-0395-8436)
- Hongfei Zhu (ORCID: https://orcid.org/0000-0002-1530-9129)
- Xuan-Yu Meng (ORCID: https://orcid.org/0000-0003-1644-6552)
- Shuqun Cheng (ORCID: https://orcid.org/0000-0001-6760-7470)
- Xubiao Wei (ORCID: https://orcid.org/0000-0002-4300-9676)
- Zonghan Liu (ORCID: https://orcid.org/0000-0003-2553-8993)
- Kaixiao Zhou (ORCID: https://orcid.org/0000-0003-2273-2985)
- Yabo Jiang
- Jinkai Feng
- Nan Yuan
- Yang Jiao (ORCID: https://orcid.org/0000-0002-1564-9174)
- Bin Zhou (ORCID: https://orcid.org/0000-0003-1293-9990)
- Yecheng Li (ORCID: https://orcid.org/0000-0003-3578-3714)
- Juxian Sun
- Chang Liu (ORCID: https://orcid.org/0000-0003-0650-1773)
Institutions
- Second Military Medical University (CN)
- Soochow University (CN)
- Second Affiliated Hospital of Soochow University (CN)
- Eastern Hepatobiliary Surgery Hospital (CN)
Publication Details
- Journal
- Molecular Therapy
- Published
- 2025-11-07
- DOI
- https://doi.org/10.1016/j.ymthe.2025.10.049
- Citations
- 1
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.94