{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:53:31Z","timestamp":1791204811332,"version":"4.1.0"},"reference-count":109,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Endoplasmic reticulum stress (ERS) arises when the protein-folding load, or perturbations in calcium and redox homeostasis, outpace the adaptive capacity of the endoplasmic reticulum (ER). The unfolded protein response (UPR) initially reduces secretory load and restores proteostasis. Persistent stress can redirect the same pathways toward inflammatory signaling, altered antigen processing, and potentially immunogenic cell death. We term this context-dependent transition ERS\u2013immune tolerance breaking, and propose it as a unifying framework for understanding how unresolved ERS may contribute to loss of cutaneous immune homeostasis. It is especially relevant in skin, where keratinocytes and melanocytes encounter ultraviolet radiation and oxidative injury while infiltrating immune cells face large biosynthetic demands. Evidence from vitiligo, pemphigus vulgaris, psoriasis, lupus erythematosus, and systemic sclerosis links dysregulated IRE1\u03b1, PERK, and ATF6 signaling to target-cell damage and immune amplification. In this review, we evaluate this evidence with particular attention to disease-specific mechanisms and the strength of causal inference supporting a pathogenic role for ERS. The case for a pathogenic role is strongest when ERS has been manipulated in defined cell types or experimental models; associations based only on UPR markers in lesions remain harder to interpret. Therapeutic studies also caution against treating the UPR as a uniformly harmful pathway. Intervention will probably need to preserve adaptive proteostasis while limiting the pathogenic output that predominates in a particular cell population and disease phase.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1980040","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:16:21Z","timestamp":1791202581000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Endoplasmic reticulum stress in autoimmune skin diseases: immune activation, cutaneous cell damage, and therapeutic advances"],"prefix":"10.3389","volume":"17","author":[{"given":"Jiaxi","family":"Qiao","sequence":"first","affiliation":[{"name":"Department of Dermatology, Traditional Chinese and Western Medicine Hospital, Hubei University of Chinese Medicine","place":["Wuhan, Hubei, China"]},{"name":"Hubei Province & Key Laboratory of Skin Infection and Immunity","place":["Wuhan, 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