Hsa_circ_0003258 drives serine biosynthesis and docetaxel resistance in prostate cancer by enhancing IGF2BP3-mediated PSAT1 mRNA stability

Background Docetaxel (DTX)-based therapy remains first-line treatment for advanced prostate cancer (PCa), yet its efficacy is often compromised by chemoresistance. Emerging evidence highlights that circular RNAs (circRNAs) contribute to the development of chemoresistance, but their specific functions in DTX-resistant PCa remain poorly understood. Methods By integrating molecular biology, cell biology, and immunology approaches, we investigated the mechanism by which hsa_circ_0003258 drives DTX resistance in PCa. Results We identified hsa_circ_0003258 was significantly elevated in DTX-resistant patients of PCa. Functional experiments confirmed that hsa_circ_0003258 enhances DTX resistance both in vitro and in vivo by promoting cancer stem-like properties, independent of its linear transcript. Mechanistically, hsa_circ_0003258 directly bound the RRMs and KH1 domains of IGF2BP3 via its CAUU motif, augmenting the non-competitive interaction between IGF2BP3’s KH4 domain and the 3’UTR of PSAT1 mRNA. This led to increased PSAT1 mRNA stability and activation of the serine biosynthesis, thereby reinforcing stemness and driving DTX resistance of PCa. To explore therapeutic potential, we engineered targeted nanoliposomes (HA-LNP@si-hsa_circ_0003258/cy7) which selectively accumulated in PCa xenografts and significantly inhibited tumor growth in combination with DTX. Co-treatment with Bix, a G9a inhibitor previously reported to suppress PSAT1 expression, further enhanced the antitumor efficacy of this combination, suggesting a potential synergistic therapeutic effect. Conclusion Our findings reveal a novel hsa_circ_0003258/IGF2BP3/PSAT1 axis that enhances de novo serine synthesis and drives DTX resistance in PCa, highlighting this pathway as a promising therapeutic target.