化疗诱导的衰老促进基质僵硬和抗氧化适应，从而促进胰腺导管腺癌的化疗耐药性
Chemotherapy-induced senescence promotes stroma stiffness and antioxidant adaptation to promote chemoresistance in pancreatic ductal adenocarcinoma.
摘要(中文译文)
胰腺导管腺癌（PDAC）的化疗耐药部分由病理性基质重塑驱动，但其潜在机制仍知之甚少。在此，我们表明吉西他滨治疗诱导肿瘤细胞衰老，并通过衰老相关分泌表型激活癌相关成纤维细胞，导致进行性纤维化基质硬化。这种生物力学重编程激活机械敏感性离子通道Piezo1，引发代谢重编程，使BRG1阳性肿瘤细胞日益依赖NRF2介导的抗氧化防御。Piezo1信号促进NRF2核转位及其与BRG1的染色质重塑协同作用，从而上调SLC7A11依赖性抗氧化程序并抑制铁死亡。值得注意的是，衰老细胞清除剂ABT-263与铁死亡诱导剂Erastin联合使用，可有效瓦解BRG1-NRF2驱动的吉西他滨耐药，减轻基质纤维化，增强T细胞浸润，并在体内抑制肿瘤生长。这种衰老细胞清除-铁死亡联合策略利用了化疗后衰老PDAC的代谢脆弱性，并为靶向基质的联合治疗提供了机制依据。
Abstract
Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) is partly driven by pathological stromal remodeling, yet the underlying mechanisms remain poorly understood. 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-NRF2-driven gemcitabine resistance, alleviates stromal fibrosis, enhances T-cell infiltration, and suppresses tumor growth in vivo. This senolytic-ferroptosis approach exploits metabolic vulnerabilities in chemotherapy-aged PDAC and provides a mechanistic rationale for stroma-targeted combination therapies.
如何引用
AMA
Xinxin Liu, Zhihua Huang, Bohan Yang, Yimeng Du, Yixin Sun, Enkui Zhang, et al. Chemotherapy-induced senescence promotes stroma stiffness and antioxidant adaptation to promote chemoresistance in pancreatic ductal adenocarcinoma.. Nature communications. 2026; doi:10.1038/s41467-026-75772-5.
APA
Xinxin Liu, Zhihua Huang, Bohan Yang, Yimeng Du, Yixin Sun, Enkui Zhang, et al (2026). Chemotherapy-induced senescence promotes stroma stiffness and antioxidant adaptation to promote chemoresistance in pancreatic ductal adenocarcinoma.. Nature communications. https://doi.org/10.1038/s41467-026-75772-5
GB/T 7714
Xinxin Liu, Zhihua Huang, Bohan Yang, Yimeng Du, Yixin Sun, Enkui Zhang, et al. Chemotherapy-induced senescence promotes stroma stiffness and antioxidant adaptation to promote chemoresistance in pancreatic ductal adenocarcinoma.[J]. Nature communications, 2026 doi:10.1038/s41467-026-75772-5.
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