Oxidative stress and Kras mutation in Mist1+ cells act in a double-hit manner to drive gastric tumorigenesis

作者：Fan Chen, Yi Han, Jingwu Yue, Hui Zhang, Luyang Tian, Zhifa Cao, Mengwen Zhu, Wenjia Wang, Yan Meng, Liwei An, Feng Li, Huanhu Zhang, Wenqi Bai, Yanfeng Xi, Zaisheng Ye, Shi Jiao, Zhaocai Zhou · 发表于：Cell Reports · 年份：2025 · DOI：10.1016/j.celrep.2025.116014 · 被引用次数：4 · 研究领域：Hippo pathway signaling and YAP/TAZ、Ferroptosis and cancer prognosis、RNA Research and Splicing

Oxidative stress is a "double-edged sword" in mediating cellular activities. Here, we report that Mist1 + cells are resistant to oxidative-stress-induced cell death and that persistent oxidative stress and Kras mutation act in Knudson's "two-hit" paradigm to promote gastric cancer initiation. Reactive oxygen species (ROS) accumulation causes metaplastic lineage expansion of Mist1 + cells, licensing them as a cellular origin of gastric cancer. Mechanistically, the transcription factor Mist1 upregulates its downstream target genes Bnip3 and Tmed6 , enhancing ROS resistance. Persistent ROS induce R-loop accumulation and activate YAP signaling in Mist1 + cells for proliferation and tumorigenesis. Importantly, ROS and Kras mutation synergistically drive the malignant transformation of Mist1 + cells, while ROS or Kras mutation alone could not do so. Collectively, our study offers insights into the two-hit theory by demonstrating that oxidative stress and oncogenic mutation cooperatively drive Mist1 + cell expansion and transcriptional reprogramming—critical events during early tumor initiation.