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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\u2010 dependent maintenance of pancreatic cancer stemness. Mechanistically, gemcitabine activates AMP\u2010activated protein kinase (AMPK), which contributes to the enhancement of STYK1\u2010mediated autophagic flux, thereby promoting stemness\u2010associated chemoresistance. Furthermore, AMPK phosphorylates STYK1 at residues Ser91 and Ser304, thereby further potentiating STYK1\u2010mediated autophagy and cancer stemness. Importantly, we developed SAIDP5, a therapeutic peptide disrupting STYK1\u2010AMPK binding, which synergizes with gemcitabine to attenuate chemoresistance. This study reveals that gemcitabine\u2010induced AMPK activation amplifies STYK1\u2010driven autophagy and cancer stemness, thereby contributing to gemcitabine resistance, and highlights SAIDP5 as a promising peptide\u2010based strategy to improve gemcitabine efficacy in PDAC.<\/jats:p>","DOI":"10.1002\/advs.202521488","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T03:54:32Z","timestamp":1791777272000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phosphorylated STYK1 Promotes Gemcitabine Resistance via Autophagy\u2010Mediated Cancer Stemness in Pancreatic Cancer"],"prefix":"10.1002","author":[{"given":"Xueying","family":"Dong","sequence":"first","affiliation":[{"name":"National \u201c111\u201d Center for Cellular Regulation and Molecular Pharmaceutics Key Laboratory of Fermentation Engineering (Ministry of Education) Hubei University of Technology  Wuhan 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