ER Stress Ire1‐Xbp1s Pathway Maintains Youthful Epidermal Basal Layer Through the Regulation of Cell Proliferation

The endoplasmic reticulum (ER) stress‐response is an adaptive cellular mechanism activated by an accumulation of unfolded proteins within the ER. Although recent evidence shows that the ER stress‐response 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‐response during aging remain unclear. To address this research gap, we introduced an Ire1‐Xbp1s ER stress‐response pathway‐sensitive reporter into the ultra‐short‐lived vertebrate Nothobranchius furzeri that allows for the analysis of its aging processes within a short period of time. Using this reporter in N. furzeri , we confirmed the previously reported age‐dependent activation of ER stress in various tissues and identified an unexpected role of the Ire1‐Xbp1s ER stress‐response pathway in regulating epidermal tissue homeostasis and aging. The Ire1‐Xbp1s ER stress‐response pathway is active in the young epidermal basal layer but declines with aging. Photo‐isolation chemistry‐based spatial transcriptomics and functional assays revealed that the Ire1‐Xbp1s pathway maintains young epidermal cell proliferation by activating the cell cycle regulator Vcp, whereas the age‐dependent decline in glucose metabolism reduces Ire1‐Xbp1s activity, consequently downregulating cell proliferation. Collectively, our study elucidates a previously unidentified role of the ER stress‐response in skin aging, which can offer insights into therapeutic targets for promoting healthy skin.