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Using integrative single\u2010cell RNA sequencing, we identified that the upregulation of mitochondrial calcium uniporter (MCU) may contribute to chemoresistance and stemness maintenance in PDAC. MCU was highly expressed in chemotherapy\u2010resistant PDAC tumors and correlated with enhanced cancer stem cell properties. Mechanistically, MCU\u2010mediated mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx triggered endoplasmic reticulum (ER) stress and the downstream PERK\u2010eIF2\u03b1 pathway. This cascade activated ATF4 and NRF2, which enhanced the transcriptional regulation of PSAT1 and SLC7A11. These changes promoted\n                    <jats:italic>de novo<\/jats:italic>\n                    glutathione (GSH) synthesis to scavenge\u00a0reactive oxygen species (ROS) and sustain stemness. Genetic knockdown or pharmacological inhibition of MCU disrupted GSH synthesis, suppressed stemness, and restored sensitivity to nab\u2010paclitaxel plus gemcitabine (AG). High\u2010throughput screening identified MCU inhibitor NB\u2010598, which synergized with AG to inhibit tumor growth in preclinical models. These findings offer a potential novel therapeutic strategy to address chemoresistance in PDAC.\n                  <\/jats:p>","DOI":"10.1002\/advs.202507346","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T09:32:52Z","timestamp":1768987972000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mitochondrial Calcium Uniporter Drives Chemoresistance in Pancreatic Cancer via Glutathione\u2010Mediated Stemness Maintenance"],"prefix":"10.1002","volume":"13","author":[{"given":"Zekun","family":"Li","sequence":"first","affiliation":[{"name":"Pancreas Center National Clinical Research Center for Cancer State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine Tianjin Medical University Cancer Institute and Hospital Tianjin Key Laboratory of Digestive Cancer Tianjin's Clinical Research Center for Cancer  Tianjin 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