AKR1C3-PKM2-oxidative phosphorylation axis drives prostate cancer radioresistance via UBE2T upregulation.

Radioresistance is one of the primary causes of prostate cancer treatment failure and post-radiotherapy progression. However, there is currently a lack of effective targets to increase radiotherapy sensitivity and inhibit malignant progression. We identified AKR1C3 as a potential key target associated with radioresistance and malignant progression through integrated bioinformatic analysis of RNA sequencing (RNA-seq) data from prostate cancer clinical samples in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The promotion of radioresistance by AKR1C3 in both AR-positive and AR-negative prostate cancer cells was further validated through in vivo and in vitro experiments. Mechanistic studies revealed that AKR1C3 can bind to PKM2 and accelerate its degradation, thereby inhibiting glycolytic flux and enhancing oxidative phosphorylation (OXPHOS). Increased OXPHOS boosts ROS production, which further promotes NRF2 nuclear translocation, activating the transcription of DNA repair protein UBE2T. This enhanced DNA damage repair ability enables prostate cancer cells with high AKR1C3 expression to exhibit greater resistance to radiotherapy. In summary, this study reveals the molecular mechanism by which AKR1C3 is involved in metabolic reprogramming to promote radioresistance in prostate cancer through PKM2/UBE2T. These findings indicate that targeting AKR1C3 has potential for overcoming radioresistance, providing novel insight into the clinical treatment of prostate cancer.