Diet-metabolism-transcription axis modulates the sensitivity to CDK4/6 inhibitors through RB1 in prostate cancer

A high-fat diet (HFD) promotes tumor progression and therapeutic resistance, but its mechanistic role in prostate cancer (PCa) remains unclear. In this study, we show that an HFD not only accelerates PCa progression but also significantly reduces sensitivity to CDK4/6 inhibitors. Mechanistically, an HFD activates CDK4, inducing RB1 phosphorylation and facilitating E2F1 release. Meanwhile, phosphorylation of RB1 at the S249/T252 site enhances its interaction with ETS1 and suppresses ETS1's transcriptional activity. Treatment with CDK4/6 inhibitors induces dephosphorylation at this site, relieving ETS1 suppression and promoting PCYT2 expression and phosphatidylcholine metabolic reprogramming. The resulting metabolic products further disrupt RB1-E2F1 binding, leading to additional E2F1 release and increased resistance to CDK4/6 inhibitors. In conclusion, our results identify a diet-metabolism-transcriptional regulatory axis centered on RB1 phosphorylation and ETS1 reactivation, reveal a mechanism of acquired resistance to CDK4/6 inhibitors of castration-resistant PCa, and provide a theoretical basis for combinatorial strategies targeting metabolic and oncogenic signals.