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Deregulated cellular bioenergetics is a hallmark of cancer cells. However, the influence of bioenergetics on the maintenance of pancreatic CSC stemness and its underlying mechanisms have not been fully elucidated. In this study, pancreatic CSCs, isolated either by sorting ALDH\n                    <jats:sup>+<\/jats:sup>\n                    subpopulation or enriching serially passaged tumorspheres from pancreatic cancer cells and PDX model, exhibited active mitochondrial complex I activity and increased oxidative phosphorylation. Complex I maintains stemness and tumorigenicity through its core subunit, NDUFS1. NDUFS1\u2010mediated pancreatic CSC stemness is reinforced by high expression of CD147, which promotes pSTAT3\n                    <jats:sup>Tyr705<\/jats:sup>\n                    \u2010mediated\n                    <jats:italic>NDUFS1<\/jats:italic>\n                    transcription. To promote stemness, CD147\u2010NDUFS1 initiates SIRT1\u2010DNMT1 metaboloepigenetic signaling, decreasing promoter hypomethylation and increasing the mRNA expression of the stem cell transcript factor\n                    <jats:italic>PAX2<\/jats:italic>\n                    . Moreover,\n                    <jats:italic>NDUFS1<\/jats:italic>\n                    and\n                    <jats:italic>CD147<\/jats:italic>\n                    expressions were highly correlated in pancreatic cancer tissues, and their co\u2010expression was significantly associated with poor patient survival. Taken together, our study provides evidence that mitochondrial complex I functions as a key player in CSC stemness maintenance through NDUFS1\u2010mediated retrograde metaboloepigenetic signaling. Blocking a key regulator of mitonuclear communication by targeting CD147 may be a novel therapy for pancreatic cancer.\n                  <\/jats:p>","DOI":"10.1002\/mco2.70678","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T08:50:01Z","timestamp":1773823801000},"source":"Crossref","is-referenced-by-count":0,"title":["NDUFS1\u2010Mediated Mitochondrial Complex I Activity Maintains Pancreatic Cancer Stemness by Promoting PAX2 Hypomethylation"],"prefix":"10.1002","volume":"7","author":[{"given":"Xin\u2010Yu","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Cell Biology National Translational Science Center for Molecular Medicine State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancer State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases Fourth Military Medical University  Xi'an 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