Circular RNA-based Therapy Targeting Metabolic Vulnerability of Fatty Acid Synthesis Overcomes Castration-Resistant Prostate Cancer

The androgen receptor (AR) signaling pathway is essential for the growth of prostate cancer (PCa) cells and remains a critical therapeutic target for castration-resistant prostate cancer (CRPC). Although circular RNAs (circRNAs) have attracted increasing attention as important regulatory molecules, their role in the AR signaling pathway during prostate cancer progression remains poorly understood.

Recently, researchers from Zhejiang University, China, published a research paper titled "Circular RNA-based therapy targeting metabolic vulnerability of fatty acid synthesis overcomes castration-resistant prostate cancer" online in PNAS. The study identified an AR-repressed circRNA, circUTRN, which is upregulated after neoadjuvant hormone therapy (NHT) but downregulated in prostate cancer tissues. circUTRN can inhibit the proliferation of both castration-sensitive and castration-resistant prostate cancer cells.

Mechanistically, circUTRN binds to acetyl-CoA carboxylase 1 (ACC1) and impairs its activity through both phosphorylation-dependent and independent pathways, thereby interfering with de novo fatty acid synthesis. The dynamic relationship between circUTRN and ACC1 expression during the progression of prostate cancer from a treatment-naive state to a treatment-resistant state highlights the metabolic vulnerability of fatty acid synthesis. Notably, the authors developed nanoparticles to deliver circUTRN and used them in combination with AR signaling inhibitors (ARSIs). This approach effectively inhibited the growth of CRPC xenografts, even in models resistant to next-generation ARSIs. This study reveals an AR-regulated circRNA involved in prostate cancer progression and proposes a potential therapeutic strategy for treatment-resistant prostate cancer.

The androgen receptor (AR) is a ligand-activated transcription factor that plays a key role in prostate cancer (PCa). Although androgen deprivation therapy (ADT) remains the most effective first-line treatment for castration-sensitive prostate cancer (CSPC), the emergence of castration-resistant prostate cancer (CRPC) is common and often fatal. The progression to CRPC usually remains dependent on the AR signaling pathway, which drives cancer cell survival and proliferation. Despite next-generation AR signaling inhibitors (ARSIs) such as enzalutamide and abiraterone further suppressing AR activity in CRPC and extending survival, drug resistance inevitably develops. At this stage, while most tumors maintain AR transcriptional activity, therapeutic options become very limited. Currently, the understanding of the AR-regulated gene profile and the molecular mechanisms involved in prostate cancer progression is still incomplete.

Metabolic reprogramming is a hallmark of cancer cells that creates therapeutic vulnerabilities. Unlike other cancers that primarily rely on glucose metabolism, prostate cancer shows limited uptake in fluorodeoxyglucose positron emission tomography (FDG-PET). Instead, AR orchestrates a unique metabolic signature in prostate cancer characterized by high levels of de novo fatty acid synthesis. Although fatty acid synthesis is vital for prostate cancer progression, its regulatory mechanisms and targeted therapeutic strategies remain unclear.

Figure 1. Characteristics of PSMA-LNPs and their in vivo application for targeting CRPC. (Lin Y, et al., 2026)

Circular RNAs (circRNAs) are covalently closed RNA molecules formed by back-splicing, characterized by high stability and functions distinct from linear mRNA. These molecules can act as competitive endogenous RNAs, transcriptional regulators, or protein-binding platforms. Although recent studies have begun to uncover the links between circRNAs and the AR signaling pathway, the regulatory networks involving AR during hormone therapy remain unclear. Furthermore, despite the potential of circRNAs as biomarkers and therapeutic targets, their clinical application still faces significant challenges.

In this study, researchers identified a circRNA derived from UTRN, named circUTRN, which is negatively regulated by the AR inhibitory complex and significantly downregulated in human prostate cancer. circUTRN can inhibit prostate cancer cell proliferation and promote apoptosis. Mechanistically, circUTRN inhibits the activity of ACC1 through phosphorylation-dependent and independent pathways, thereby impairing de novo fatty acid biosynthesis. Using bioinformatics analysis and serially transplanted CRPC xenograft models, they mapped the dynamic expression profiles of circUTRN and ACC1 during the transition from CSPC to CRPC. Based on these findings, the researchers developed prostate-specific membrane antigen (PSMA) ligand-coated nanoparticles for the delivery of circUTRN to treat CRPC and enzalutamide-resistant CRPC xenograft models in vivo.

Reference

Lin Y, et al. Circular RNA–based therapy targeting metabolic vulnerability of fatty acid synthesis overcomes castration-resistant prostate cancer. Proceedings of the National Academy of Sciences, 2026, 123(1): e2504904123.