CircPPFIA2 drives prostate cancer progression and enzalutamide resistance by sponging miR-646 and miR-1200 to upregulate ETS1

Abstract Prostate cancer (PCa) represents a leading cause of cancer-related morbidity in men worldwide, necessitating deeper insights into its molecular drivers. Circular RNAs (circRNAs) are increasingly recognized as key regulatory molecules in carcinogenesis; however, their functional significance in PCa pathogenesis and treatment resistance remains incompletely defined. Here, we identify circPPFIA2 as a novel clinically relevant oncogenic circRNA with dual roles in PCa progression and therapeutic resistance. CircPPFIA2 is markedly upregulated in PCa clinical specimens and cell lines. Through gain- and loss-of-function experiments in both cell-based and animal models, we established that circPPFIA2 drives oncogenic phenotypes by enhancing tumor cell proliferation, migratory capacity, and resistance to enzalutamide therapy. Mechanistic investigations revealed that circPPFIA2 functions as a competitive endogenous RNA (ceRNA), simultaneously sequestering tumor-suppressive miR-646 and miR-1200. This miRNA sponge activity facilitates post-transcriptional upregulation of ETS1, a critical effector of androgen receptor signaling and treatment resistance. This molecular interplay establishes the circPPFIA2/miR-646/miR-1200/ETS1 axis as a central driver of PCa progression and therapy resistance. To functionally validate this finding, we employed lipid nanoparticle (LNP)-mediated co-delivery of si-circPPFIA2 and enzalutamide, which effectively restored drug sensitivity and inhibited tumor growth in resistant PCa models. Our findings highlight circPPFIA2 as both a prognostic biomarker and a promising therapeutic target for advanced PCa, providing a rationale for developing circRNA-directed therapies to overcome treatment resistance.