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

作者：Yabo Jiang, Kaixiao Zhou, Xubiao Wei, Jinkai Feng, Bin Zhou, Chang Liu, Juxian Sun, Hongfei Zhu, Zonghan Liu, Nan Yuan, Yecheng Li, Xuan-Yu Meng, Jianping Cao, Yang Jiao, Shuqun Cheng · 发表于：Molecular Therapy · 年份：2025 · DOI：10.1016/j.ymthe.2025.10.049 · 被引用次数：3 · 研究领域：Cancer, Hypoxia, and Metabolism、Protein Kinase Regulation and GTPase Signaling、ATP Synthase and ATPases Research

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.