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Human keratocytes were exposed to nigericin, and cell death was assessed through morphological analysis and detection of related molecular markers. Proteomic profiling was performed to identify cell death\u2010related proteins, with key findings validated by western blot. Additionally, organelle disruptions were examined using immunostaining techniques. Pyroptosis\u2010like cell death was observed morphologically in cultured keratocytes. Moreover, an elevated release of IL\u20101beta was detected, accompanied by a significant loss of mitochondrial membrane potential. However, nigericin treatment induced a form of non\u2010inflammatory cell death characterized by extensive vacuolation, resembling paraptosis. This was accompanied by the absence of caspase\u20103 activation and endoplasmic reticulum (ER) stress markers, along with increased accumulation of the autophagic marker LC3\u2010II. Proteomic analysis revealed the absence of key components of the canonical pyroptosis pathway, including proteins involved in inflammasome assembly and the gasdermin (GSDM) family. These results were further confirmed by western blot. Significant alterations were also observed in the Golgi apparatus, mitochondria, and lysosomes following nigericin treatment. These findings suggest that nigericin triggers a paraptosis\u2010like cell death in human keratocytes, rather than pyroptosis, as keratocytes lack the canonical executors of pyroptosis. This highlights an alternative mechanism of cell death in the cornea, warranting further exploration to understand its role and potential therapeutic implications.<\/jats:p>","DOI":"10.1096\/fj.202500502r","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T11:40:10Z","timestamp":1750419610000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nigericin Induces Paraptosis\u2010Like Cell Death Instead of Pyroptosis in Corneal Keratocytes"],"prefix":"10.1096","volume":"39","author":[{"given":"Xiangquan","family":"Mi","sequence":"first","affiliation":[{"name":"Medical College Shihezi University  Shihezi China"},{"name":"Department of Medical and Translational Biology Ume\u00e5 University  Ume\u00e5 Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1617-334X","authenticated-orcid":false,"given":"Xin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Medical and Translational Biology Ume\u00e5 University  Ume\u00e5 Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaochun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Chemistry Ume\u00e5 University  Ume\u00e5 Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andre","family":"Mateus","sequence":"additional","affiliation":[{"name":"Department of Chemistry Ume\u00e5 University  Ume\u00e5 Sweden"},{"name":"The Laboratory for Molecular Infection Medicine Sweden (MIMS), Ume\u00e5 University  Ume\u00e5 Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6091-3982","authenticated-orcid":false,"given":"Ludvig J.","family":"Backman","sequence":"additional","affiliation":[{"name":"Department of Medical and Translational Biology Ume\u00e5 University  Ume\u00e5 Sweden"},{"name":"Department of Community Medicine and Rehabilitation Ume\u00e5 University  Ume\u00e5 Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7906-9152","authenticated-orcid":false,"given":"Patrik","family":"Danielson","sequence":"additional","affiliation":[{"name":"Department of Medical and Translational Biology Ume\u00e5 University  Ume\u00e5 Sweden"},{"name":"Department of Clinical Sciences, Ophthalmology Ume\u00e5 University  Ume\u00e5 Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,6,20]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2007.06.009"},{"key":"e_1_2_11_3_1","first-page":"276","article-title":"Keratocyte Apoptosis After Corneal Surgery","volume":"39","author":"Helena M. 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