Abstract / Summary
ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with gemcitabine resistance remaining a major clinical challenge. Although cancer stemness and autophagy have both been implicated in PDAC chemoresistance, the mechanism by which their crosstalk governs gemcitabine resistance remains poorly understood. Here, we identify serine/threonine/tyrosine kinase 1 (STYK1) as a critical mediator of gemcitabine resistance through autophagy‐ dependent maintenance of pancreatic cancer stemness. Mechanistically, gemcitabine activates AMP‐activated protein kinase (AMPK), which contributes to the enhancement of STYK1‐mediated autophagic flux, thereby promoting stemness‐associated chemoresistance. Furthermore, AMPK phosphorylates STYK1 at residues Ser91 and Ser304, thereby further potentiating STYK1‐mediated autophagy and cancer stemness. Importantly, we developed SAIDP5, a therapeutic peptide disrupting STYK1‐AMPK binding, which synergizes with gemcitabine to attenuate chemoresistance. This study reveals that gemcitabine‐induced AMPK activation amplifies STYK1‐driven autophagy and cancer stemness, thereby contributing to gemcitabine resistance, and highlights SAIDP5 as a promising peptide‐based strategy to improve gemcitabine efficacy in PDAC.