TRMT1-mediated tRNA m22G modification drives Osimertinib resistance via the ATXN3/USP25 axis in lung adenocarcinoma
Abstract Acquired resistance to Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), remains a critical challenge in lung adenocarcinoma. Here, we identify ATXN3, a deubiquitinating enzyme, as a driver of Osimertinib resistance and a predictor of poor patient survival. Osimertinib treatment dynamically upregulates ATXN3 transcription, which stabilizes USP25 through deubiquitination, activating an ATXN3-USP25-TRMT1 signaling cascade. This axis enhances TRMT1-mediated tRNA m² 2 G modifications, enabling selective translation of redox-regulating enzymes (e.g., GPX4, SOD2) that scavenge reactive oxygen species (ROS) and mitigate drug-induced oxidative stress. Genetic ablation of TRMT1 or pharmacological targeting of USP25 with the small-molecule inhibitor AZ1 disrupted this pathway, restored ROS accumulation, and re-sensitized resistant tumors to Osimertinib in patient-derived organoids and in vivo models. Our findings reveal tRNA epitranscriptomic reprogramming as a novel mechanism of EGFR-TKI resistance and position the ATXN3/USP25/TRMT1 axis as a therapeutically actionable target to overcome Osimertinib resistance in lung cancer.
Authors
- Hu Lei (ORCID: https://orcid.org/0000-0003-3288-5205)
- Wenhui Bai (ORCID: https://orcid.org/0009-0007-4297-9527)
- Huishu Dong
- Yanjie Ji (ORCID: https://orcid.org/0000-0002-7172-3818)
- Y Zhang
- Hanzhang Xu (ORCID: https://orcid.org/0000-0001-9617-247X)
- M Liu
- Yingli Wu (ORCID: https://orcid.org/0000-0001-7909-8757)
- Wenxuan Wu (ORCID: https://orcid.org/0000-0003-2308-7949)
- Jiaqi Li (ORCID: https://orcid.org/0009-0005-4613-5116)
- Kuofang Huang
- Tianqing Chu (ORCID: https://orcid.org/0000-0002-1383-0383)
- Wanting Liu (ORCID: https://orcid.org/0000-0001-5565-4747)
- Hao Luo (ORCID: https://orcid.org/0000-0001-5415-7474)
- Haijiao Lu
- Yingying Wang (ORCID: https://orcid.org/0000-0002-3659-6139)
- Shifei Pan
- Yuanhui Zhai
- Bo Jing
- Chujiao Zhu
- Qiuyu Wei
- Xuxinyi Ling
- Hua Zhong
- Jialin Qian
Institutions
- Tongji University (CN)
- East China University of Science and Technology (CN)
- Shanghai Jiao Tong University (CN)
- Shanghai Chest Hospital (CN)
- Tongren Hospital (CN)
- Shanghai Cancer Institute (CN)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- Ministry of Education (TH)
- Shanghai Pulmonary Hospital (CN)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2026-06-29
- DOI
- https://doi.org/10.1038/s41419-026-09039-8
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China