Circular RNA-based therapy targeting metabolic vulnerability of fatty acid synthesis overcomes castration-resistant prostate cancer.

Abstract

Androgen receptor (AR) signaling is essential for prostate cancer (PCa) cell growth and remains a key therapeutic target in castration-resistant PCa (CRPC). While circular RNAs (circRNAs) are increasingly recognized as important regulatory molecules, their roles in AR signaling during PCa progression remain poorly understood. This study identified <i>circUTRN</i>, an AR-inhibited circRNA that is upregulated following neoadjuvant hormonal therapy and downregulated in PCa tissues. <i>circUTRN</i> inhibits proliferation in both castration-sensitive and castration-resistant PCa. Mechanistically, <i>circUTRN</i> binds to acetyl-CoA carboxylase 1 (ACC1) and impairs the activity through both phosphorylation-dependent and independent pathways, thereby disturbing de novo fatty acid synthesis. The dynamic relation between <i>circUTRN</i> and ACC1 expression during PCa progression from treatment-naïve to therapeutic-resistant states highlights the metabolic vulnerability of fatty acid synthesis. Notably, we developed nanoparticles to deliver <i>circUTRN</i> in combination with AR signaling inhibitors (ARSIs). This approach effectively suppressed CRPC xenograft tumor growth, even in models resistant to next-generation ARSIs. This study reveals an AR-regulated circRNA involved in PCa progression and suggests a potential therapeutic strategy for treatment-resistant PCa.