A novel lncRNA HUDRPC suppresses ferroptosis via the DDX5/DDIT3 pathway to promote docetaxel resistance in prostate cancer.

Docetaxel remains first-line chemotherapy for advanced prostate cancer (PCa), but acquired resistance severely limits durable clinical responses. While long non-coding RNAs (lncRNAs) are established as critical regulators of tumor chemoresistance, the specific mechanisms driving docetaxel resistance in PCa remain poorly understood. Here, we functionally characterized a novel docetaxel resistance-associated lncRNA in PCa. Through comparative transcriptome sequencing of isogenic docetaxel-sensitive and resistant PCa cell lines, we identified an uncharacterized lncRNA (RP11-151G14.2), termed HUDRPC, which was significantly upregulated in resistant cells and patient-derived tumor tissues. Loss-of-function validation confirmed that HUDRPC was required to maintain docetaxel resistance both in vitro and in vivo. Mechanistically, HUDRPC promoted docetaxel resistance by directly inhibiting ferroptosis. CRISPR-Cas9 knockout of HUDRPC markedly augmented docetaxel-induced reactive oxygen species accumulation, lipid peroxidation and iron overload, and sensitized resistant PCa cells and xenografts to docetaxel treatment. We further demonstrated that HUDRPC directly bound the RNA helicase DDX5, and recruited DDX5 to the DDIT3 promoter, thereby enhancing DDIT3 transcription in a DDX5-dependent manner. Clinically, high DDIT3 expression correlated with poorer overall survival and inferior docetaxel response in PCa patients. Rescue experiments showed that forced DDIT3 overexpression reversed HUDRPC depletion-induced ferroptosis and docetaxel sensitization, confirming DDIT3 as the key downstream effector of HUDRPC. Collectively, our findings identify the HUDRPC-DDX5- DDIT3 axis as a critical regulator of docetaxel resistance, highlighting HUDRPC as a promising prognostic biomarker and therapeutic target to overcome chemoresistance in advanced PCa.