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Here, we show that gemcitabine treatment induces tumor cell senescence and activates cancer-associated fibroblasts via the senescence-associated secretory phenotype, leading to progressive fibrotic matrix stiffening. This biomechanical reprogramming engages the mechanosensitive ion channel Piezo1, triggering metabolic rewiring that renders BRG1-positive tumor cells increasingly dependent on NRF2-mediated antioxidant defenses. Piezo1 signaling promotes NRF2 nuclear translocation and its chromatin-remodeling cooperation with BRG1, thereby upregulating SLC7A11-dependent antioxidant programs and suppressing ferroptosis. Notably, the combination of the senolytic agent ABT-263 with the ferroptosis inducer Erastin effectively dismantles BRG1\u2013NRF2-driven gemcitabine resistance, alleviates stromal fibrosis, enhances T-cell infiltration, and suppresses tumor growth in vivo. This senolytic\u2013ferroptosis approach exploits metabolic vulnerabilities in chemotherapy-aged PDAC and provides a mechanistic rationale for stroma-targeted combination therapies.<\/jats:p>","DOI":"10.1038\/s41467-026-75772-5","type":"journal-article","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T14:26:06Z","timestamp":1784384766000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Chemotherapy-induced senescence promotes stroma stiffness and antioxidant adaptation to promote chemoresistance in pancreatic ductal adenocarcinoma"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9568-6436","authenticated-orcid":false,"given":"Xinxin","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4169-3184","authenticated-orcid":false,"given":"Zhihua","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bohan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimeng","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enkui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyuan","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7233-5892","authenticated-orcid":false,"given":"Kai","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4893-8113","authenticated-orcid":false,"given":"Yongsu","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0943-5161","authenticated-orcid":false,"given":"Xiaodong","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7337-4308","authenticated-orcid":false,"given":"Xiaojie","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3722-2457","authenticated-orcid":false,"given":"Yinmo","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"75772_CR1","first-page":"e70043","volume":"76","author":"RL Siegel","year":"2026","unstructured":"Siegel, R. 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