USP10-mediated PFKFB4 deubiquitination induces lung cancer radioresistance by activating the fumarate/Rad51 axis

Radioresistance is a major cause of radiotherapy failure in lung cancer, and its mechanism has not been fully elucidated. Glucose metabolism is closely related to radioresistance, and targeting key molecules in glucose metabolism is expected to increase radiosensitivity. Our study demonstrated that the expression of the gluconeogenic enzyme PFKFB4 was upregulated in lung cancer. Genetic silencing and pharmacological inhibition of PFKFB4 significantly enhanced lung cancer radiosensitivity. Mechanistically, the fumaric acid/Rad51 axis is crucial for PFKFB4-induced radioresistance. PFKFB4 inhibits histone demethylase KDM1A by upregulating fumaric acid, which in turn increases the level of H3K4me1 at the Rad51 promoter region and induces Rad51 transcriptional activation, and ultimately leads to lung cancer radioresistance. Furthermore, by constructing a library of ubiquitinated compounds, the deubiquitinating enzyme USP10 was identified as a key upstream molecule for stabilizing PFKFB4 expression, and USP10 silencing downregulated fumaric acid and Rad51 in a PFKFB4-dependent manner, which in turn increased lung cancer radiosensitivity. In conclusion, the present study reveals that USP10-mediated PFKFB4deubiquitination promotes lung cancer radioresistance through activation of the fumaric acid/Rad51 axis and provides important evidence for the clinical translation of PFKFB4.