Loss of UFL1 confers enzalutamide resistance of prostate tumors by regulating METTL16-mediated m6A modification of EEF1A1 mRNA.

Enzalutamide (ENZ), a next-generation androgen receptor (AR) inhibitor, is a cornerstone treatment for metastatic prostate cancer. However, resistance to ENZ inevitably develops in these patients, and the mechanisms underlying this resistance remain poorly understood. This study reveals that UFL1 is dysregulated in ENZ-resistant cells, xenograft models, and prostate tumors. UFL1 deficiency enhances prostate cancer cell resistance to ENZ both in vitro and in vivo. Mechanistically, UFL1 loss decreases METTL16 UFMylation, thereby reducing its ubiquitination level and increasing its protein stability. Additionally, METTL16-mediated m6A modification of EEF1A1 mRNA activates the m6A-IGF2BP1 axis, resulting in increased EEF1A1 protein levels and enhanced resistance to ENZ-induced apoptosis. These findings uncover a novel UFL1-METTL16-EEF1A1 signaling pathway that drives ENZ resistance, suggesting that targeting this cascade may offer a promising therapeutic strategy for overcoming ENZ resistance in prostate cancer.