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In this study, we used a mitochondrial metabolomics approach to compare primary and metastatic breast cancer cells. This analysis revealed accumulation of mitochondrial glutathione (GSH) during lung metastasis, driven by elevated expression of SLC25A39, a mitochondrial GSH transporter. Loss of SLC25A39 impairs metastatic colonization in genetic screens, cell line models, and patient-derived xenografts, without affecting primary tumor growth. Mitochondrial GSH import is specifically required during early colonization and functions independently of its canonical antioxidant role. CRISPR activation screens identified ATF4, a stress-induced transcription factor, as a bypass mechanism that restores metastatic potential in SLC25A39-deficient cells. Mechanistically, SLC25A39 is required for optimal ATF4 activation during metastasis and under hypoxia, linking mitochondrial GSH availability to integrated stress response signaling. These findings identify mitochondrial GSH as a necessary and limiting metabolite for metastatic progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Mitochondrial GSH import via SLC25A39 is essential for early metastatic colonization in breast cancer, linking metabolic adaptation to stress response signaling. Targeting this pathway may uncover a therapeutic vulnerability specific to metastasis without affecting primary tumor growth.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-1556","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T11:12:43Z","timestamp":1753873963000},"page":"2437-2449","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Mitochondrial Glutathione Import Enables Breast Cancer Metastasis via Integrated Stress Response Signaling"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5535-5245","authenticated-orcid":false,"given":"Hsi-wen","family":"Yeh","sequence":"first","affiliation":[{"name":"1Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, New 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