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However, the molecular alterations in PanIN lesions and their contribution to PDAC progression remain poorly defined. Here, using laser capture microdissection\u2010based proteomics of patient tissues, early metabolic remodeling and upregulation of the transcriptional factor specificity protein 1 (SP1) in PanIN lesions are identified, which persisted into the PDAC stage. That SP1 overexpression promoted PDAC proliferation is demonstrated in patient\u2010derived organoid xenograft models (PDOXs), while deletion of Sp1 inhibited tumorigenesis and progression in a transgenic mouse model of PDAC (\n                    <jats:italic>\n                      Kras\n                      <jats:sup>LSL\u2010G12D\/+<\/jats:sup>\n                      ; Trp53\n                      <jats:sup>LSL\u2010R172H\/+<\/jats:sup>\n                      ; Sp1\n                      <jats:sup>LOXP\/LOXP<\/jats:sup>\n                      ; Pdx1\u2010Cre\n                    <\/jats:italic>\n                    ). ChIP\u2010seq and isotope tracing revealed that SP1 enhances aerobic glycolysis by transcriptionally activating 6\u2010phosphofructo\u20102\u2010kinase\/fructose\u20102,6\u2010bisphosphatase (PFKFB4), a key regulator of glycolysis. Combination therapy targeting SP1 and PFKFB4 demonstrated significant efficacy in PDAC models in vivo. The findings suggest that SP1 is a critical regulator of PDAC initiation and progression through its control of metabolic remodeling. Targeting SP1 and PFKFB4 represents a promising therapeutic strategy for PDAC treatment.\n                  <\/jats:p>","DOI":"10.1002\/advs.202510071","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T09:52:36Z","timestamp":1755683556000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["SP1\u2010Mediated Glycolytic Reprogramming Promotes Tumorigenesis and Progression in Pancreatic Cancer"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1329-4880","authenticated-orcid":false,"given":"Hexing","family":"Hang","sequence":"first","affiliation":[{"name":"Department of Pancreatic and Metabolic Surgery Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University Nanjing Jiangsu 210008 China"},{"name":"Department of Pathology Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University Nanjing Jiangsu 210008 China"},{"name":"Jiangsu Key Laboratory of Molecular Medicine Medical School Nanjing University Nanjing Jiangsu 210093 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyu","family":"Yu","sequence":"additional","affiliation":[{"name":"The Affiliated Jiangning Hospital of Nanjing Medical University Nanjing Jiangsu 211100 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linxi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Molecular Medicine Medical School Nanjing University Nanjing Jiangsu 210093 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neng","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pancreatic and Metabolic Surgery Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University Nanjing Jiangsu 210008 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Pancreatic and Metabolic Surgery Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University Nanjing Jiangsu 210008 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenghua","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Pancreatic and Metabolic Surgery Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University Nanjing Jiangsu 210008 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghao","family":"Yan","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Molecular Medicine Medical School Nanjing University Nanjing Jiangsu 210093 China"},{"name":"Immunology and Reproduction Biology Laboratory &amp; 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