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Here, we investigated IRE1 and XBP1 signaling in MDA-MB-231 cells exposed to palmitate and etoposide. Under combined lipotoxic and genotoxic stress, XBP1 depletion increased DNA-damage accumulation in IRE1 wild-type cells but not in IRE1-deficient cells, whereas IRE1 re-expression reduced DNA damage. Pharmacologic IRE1 RNase inhibition also increased etoposide-associated DNA damage, supporting a protective role for IRE1 RNase-dependent signaling. IRE1 status and XBP1 manipulation differentially affected H2A.X and \u03b3H2A.X abundance, indicating context-dependent regulation of chromatin-associated DNA-damage signaling. At the RNA level, H2A.X was enriched in IRE1 immunoprecipitates, and the H2A.X-linked DNA-damage-response transcripts HUWE1 and BRCA2 also associated with IRE1 under combined stress. These findings link palmitate-activated IRE1-XBP1 signaling to genome-protective responses during genotoxic stress and identify a network of IRE1-associated DNA-damage-response transcripts in triple-negative breast cancer cells. Direct IRE1-mediated cleavage of these transcripts remains to be established.<\/jats:p>","DOI":"10.64898\/2026.09.25.754433","type":"posted-content","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T10:25:11Z","timestamp":1790591111000},"source":"Crossref","is-referenced-by-count":0,"title":["Palmitate-activated IRE1-XBP1 signaling limits DNA damage and is associated with H2A.X-linked DNA damage response transcripts in triple-negative breast cancer cells"],"prefix":"10.64898","author":[{"given":"Kevin Y.","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaina","family":"Gouin","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ava","family":"Erickson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Michigan State University, MI, USA"},{"name":"Department Microbiology, Genetics, & Immunology, Michigan State University, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yogit","family":"Goyal","sequence":"additional","affiliation":[{"name":"Department Microbiology, Genetics, & Immunology, Michigan State University, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Zaloudek","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Foster","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb","family":"Sandum","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Materials Science, Michigan State University, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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