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Although recent evidence shows that the ER stress\u2010response is activated in aged tissues, and therefore ER stress is considered a candidate driver of aging, the spatiotemporal regulation and roles of the ER stress\u2010response during aging remain unclear. To address this research gap, we introduced an Ire1\u2010Xbp1s ER stress\u2010response pathway\u2010sensitive reporter into the ultra\u2010short\u2010lived vertebrate\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Nothobranchius furzeri<\/jats:italic>\n                    <\/jats:styled-content>\n                    that allows for the analysis of its aging processes within a short period of time. Using this reporter in\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>N. furzeri<\/jats:italic>\n                    <\/jats:styled-content>\n                    , we confirmed the previously reported age\u2010dependent activation of ER stress in various tissues and identified an unexpected role of the Ire1\u2010Xbp1s ER stress\u2010response pathway in regulating epidermal tissue homeostasis and aging. The Ire1\u2010Xbp1s ER stress\u2010response pathway is active in the young epidermal basal layer but declines with aging. Photo\u2010isolation chemistry\u2010based spatial transcriptomics and functional assays revealed that the Ire1\u2010Xbp1s pathway maintains young epidermal cell proliferation by activating the cell cycle regulator Vcp, whereas the age\u2010dependent decline in glucose metabolism reduces Ire1\u2010Xbp1s activity, consequently downregulating cell proliferation. Collectively, our study elucidates a previously unidentified role of the ER stress\u2010response in skin aging, which can offer insights into therapeutic targets for promoting healthy skin.\n                  <\/jats:p>","DOI":"10.1111\/acel.70258","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T04:56:15Z","timestamp":1760331375000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>ER<\/scp>\n                    Stress Ire1\u2010Xbp1s Pathway Maintains Youthful Epidermal Basal Layer Through the Regulation of Cell Proliferation"],"prefix":"10.1111","volume":"24","author":[{"given":"Daniel","family":"Semmy","sequence":"first","affiliation":[{"name":"Department of Homeostatic Regulation, Research Institute of Microbial Diseases Osaka University  Osaka 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University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8914-5047","authenticated-orcid":false,"given":"Tobias Clausen","family":"Mercurio","sequence":"additional","affiliation":[{"name":"Department of Homeostatic Regulation, Research Institute of Microbial Diseases Osaka University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyosuke","family":"Asakawa","sequence":"additional","affiliation":[{"name":"Division of Aging and Regeneration, Institute of Medical Science The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emi K.","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Division of Aging and Regeneration, Institute of Medical Science The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Oki","sequence":"additional","affiliation":[{"name":"Division of 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