PFKFB4 Deubiquitination by USP10 Enhances Fumarate Metabolism to Orchestrate the KDM1A/Rad51 Axis and Confer Radioresistance in Lung Cancer

ABSTRACT Aberrant glucose metabolism reprogramming is a key driver of radioresistance, which is a major obstacle in lung cancer treatment. As a central glucose metabolic regulator, the specific function and molecular mechanisms of PFKFB4 in this process remain undefined. This study revealed that PFKFB4 is aberrantly overexpressed in lung cancer and that targeted inhibition of PFKFB4 enhances radiosensitivity both in vitro and in vivo. Mechanistically, PFKFB4 upregulates fumarate by driving the ATP‐dependent urea cycle. Accumulated fumarate inhibits the histone demethylase KDM1A, leading to increased enrichment of H3K4me1 at the Rad51 promoter and the subsequent transcriptional activation of Rad51, thereby promoting radioresistance. Furthermore, a ubiquitin library screen revealed that the deubiquitinase USP10 is an upstream regulator that binds and stabilizes PFKFB4 by deubiquitinating PFKFB4 at residue K431. Consequently, USP10 depletion increases radiosensitivity by disrupting the PFKFB4/fumarate/Rad51 axis. In summary, this study elucidates the mechanism by which PFKFB4 overexpression confers radioresistance in lung cancer, providing a rationale for targeting this protein in the clinical treatment of lung cancer patients.