ASO Therapy Targeting STAU2 to Inhibit Pancreatic Ductal Adenocarcinoma Progression and Metastasis by Regulating the PALLD‐Mediated EMT Signaling Pathway

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy marked by high morbidity, recurrence, and metastasis, with limited treatment options and poor prognosis. The challenge of early diagnosis and the inefficacy of current therapeutic strategies underscore the urgent need for novel biomarkers and therapeutic targets. RNA‐binding proteins (RBPs) are emerging as critical regulators of post‐transcriptional processes and are implicated in cancer progression. Here, the study identifies Staufen Double‐Stranded RNA Binding Protein 2 (STAU2) as an oncogenic RBP with high expression in PDAC, which is significantly associated with metastasis. It is demonstrated that STAU2 directly binds and regulates cytoskeletal associated protein Palladin (PALLD) and mediates IQ motif containing GTPase‐activating protein 1 (IQGAP1), thereby promoting metastasis via the epithelial‐mesenchymal transition (EMT) pathway. Moreover, a 2′‐methoxyethoxy (2′‐MOE)‐modified antisense oligonucleotide (ASO) targeting STAU2 is developed, which effectively inhibited downstream targets in vitro and in vivo. STAU2‐ASO treatment significantly suppressed PDAC progression and metastasis, with a demonstrated safety profile in vivo.