Recently, a collaborative team led by Professor Jianping Cao from the State Key Laboratory of Radiation Medicine and Protection, Soochow University, and Professor Shuqun Cheng from the Third Affiliated Hospital of Naval Medical University has made new progress in unraveling the mechanism of radiotherapy resistance in hepatocellular carcinoma (HCC). The related findings were published in the journal Molecular Therapy under the title "RAC1 Directly Phosphorylates Both PKM2 and FBP1 to Promote Radioresistance in Hepatocellular Carcinoma" (DOI: https://doi.org/10.1016/j.ymthe.2025.10.049)
In hepatocellular carcinoma, radiotherapy resistance of tumor cells is a major cause of treatment failure. This study is the first to identify that RAC1 is significantly overexpressed in HCC patients insensitive to radiotherapy, highlighting its critical role in radioresistant HCC. RAC1, endowed with both GTPase and novel protein kinase activities, bidirectionally regulates PKM2 (S172 phosphorylation enhances glycolysis) and FBP1 (T309 phosphorylation inhibits gluconeogenesis). This regulation markedly elevates the glucose metabolism level of tumor cells, enabling them to maintain a survival advantage under radiotherapy stress. Based on this innovative mechanistic discovery, the team employed high-throughput virtual screening to identify foscarnet sodium, an FDA-approved drug. They verified that foscarnet sodium can effectively reverse radiotherapy resistance by targeting and inhibiting RAC1 activity. When combined with radiotherapy in HCC models, it exhibits a significant synergistic tumor-suppressive effect, providing an original therapeutic strategy to address the clinical challenge of radiotherapy resistance in HCC.
Figure 1: Schematic diagram illustrating the mechanism by which RAC1 mediates metabolic reprogramming through phosphorylating PKM2 and FBP1 to promote radiotherapy resistance in HCC
Corresponding authors of this paper are Professor Yang Jiao and Professor Jianping Cao from the School of Radiation Medicine and Protection, Soochow University, and Professor Shuqun Cheng from the Third Affiliated Hospital of Naval Medical University. The first author is attending physician Yabo Jiang from the Third Affiliated Hospital of Naval Medical University. Co-first authors include Dr. Kaixiao Zhou from the School of Radiation Medicine and Protection, Soochow University, associate chief physician Xubiao Wei, and Dr. Jinkai Feng from the Third Affiliated Hospital of Naval Medical University.
This research work was supported by the National Key Research and Development Program of China and the National Natural Science Foundation of China.
Contributor: Kaixiao Zhou; First Reviewer: Yang Jiao; Reviewer: Chenggui Wang; First Proofreader: Yang Jiao; Second Proofreader: Jianping Cao; Proofreader: Chenggui Wang