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Induction of oxidative stress weakened intercellular adhesion, a defining characteristic of DD, which antioxidant treatment improved. Treatment with antioxidants or SERCA activators also diminished glutathionylation, consistent with SERCA2 haploinsufficiency giving rise to oxidative stress and placing residual SERCA2 at risk of oxidation. We posit that partial loss of protein activity primes cells for stress-induced loss of the remaining activity, a mechanism that may drive disease flares in other haploinsufficiencies.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aee1599","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T18:01:42Z","timestamp":1785952902000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Failed metabolic adaptation to stress contributes to epidermal cell adhesion defects in Darier disease"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4843-0168","authenticated-orcid":true,"given":"Robert M.","family":"Harmon","sequence":"first","affiliation":[{"name":"Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA."},{"name":"Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 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