ADAMTS9‐AS2 Disrupts Docetaxel‐Resistance in Castration‐Resistant Prostate Cancer via Stemness Suppression and Ferroptosis Induction

ABSTRACT Castration‐resistant prostate cancer (CRPC) chemotherapy resistance remained a significant clinical challenge. Prostate tumor stem cells (PCSCs) played a crucial role in chemotherapy resistance, but the underlying mechanisms were not fully understood. This study investigated how ADAMTS9‐AS2 reduced chemotherapy resistance in CRPC through a dual mechanism and explored the potential of polymeric materials targeting PCSCs and enhancing chemotherapy sensitivity. Key regulatory molecules of PCSCs were identified through mRNAsi‐based multi‐center patient cohorts. The effect of ADAMTS9‐AS2 on reducing docetaxel resistance in CRPC was assessed, and its mechanisms were further explored using in vitro and in vivo experiments. Finally, polymeric materials containing TGF‐β inhibitor, ferroptosis inducer, and miR‐182‐5p inhibitor were used to target PCSCs to improve chemotherapy sensitivity. ADAMTS9‐AS2 reduced CRPC chemotherapy resistance through dual mechanisms: (1) regulating FOXF2/TGF‐β2 axis to suppress PCSCs stemness; (2) encoding a short peptide that competitively retained more SLC7A11 in the cytoplasm than on the cytomembrane, thus promoting ferroptosis. Furthermore, polymeric materials targeting PCSCs significantly enhanced docetaxel sensitivity and inhibited tumor progression. ADAMTS9‐AS2 delayed docetaxel resistance by suppressing CRPC stemness and inducing ferroptosis. The use of polymeric materials targeting PCSCs offered a novel strategy to overcome CRPC chemotherapy resistance.