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Pharmacol."],"abstract":"<jats:p>Mast cells and basophils play important roles in allergic disorders associated with specific antigens and IgE. Crosslinking of the high-affinity IgE receptor (Fc\u03b5RI) by specific antigens activates several tyrosine kinases, such as Lyn and spleen-associated tyrosine kinase (Syk), resulting in the release of calcium ions (Ca<jats:sup>2+<\/jats:sup>) from the endoplasmic reticulum (ER) into the cytoplasm. As Ca<jats:sup>2+<\/jats:sup> release from the ER is essential for the release of pro-inflammatory mediators, ER stress-related molecules, such as inositol-requiring enzyme 1\u03b1 (IRE1\u03b1), may play roles in mast cell and basophil activation. However, the associations between ER stress-related molecules and mast cell and basophil activation remain unclear. In this study, we aimed to investigate the roles of ER stress-related molecules in mast cell and basophil activation. Activation of the IRE1\u03b1-spliced form of the X-box binding protein 1 (sXBP1) axis, an ER stress-related pathway, was observed during the antigen-induced activation of mast cells. Moreover, the IRE1\u03b1 inhibitor, KIRA6, suppressed antigen-induced release of pro-inflammatory mediators from rat basophilic leukemia (RBL)-2H3 cells, bone marrow-derived mast cells (BMMCs), human basophils, and human mast cells at low doses (&amp;lt;1\u00a0\u03bcM). However, to our surprise, IRE1\u03b1 knockout did not inhibit antigen-induced release of pro-inflammatory mediators. Instead, KIRA6 blocked the antigen-induced activation of Syk by inhibiting kinase activity of Lyn. Additionally, KIRA6 exerted anti-allergic effects <jats:italic>in vivo<\/jats:italic>. Overall, our findings suggest that KIRA6 prevents allergic reactions by inhibiting the kinase activity of Lyn via an IRE1\u03b1-independent pathway.<\/jats:p>","DOI":"10.3389\/fphar.2025.1625798","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T05:26:04Z","timestamp":1753421164000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Unique compound with anti-allergic action: inhibition of Lyn kinase activity by KIRA6"],"prefix":"10.3389","volume":"16","author":[{"given":"Goshi","family":"Matsushima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Matsui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanano","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagisa","family":"Umeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Kakimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megumi","family":"Mino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Nakagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshimi","family":"Matsuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiki","family":"Matsubara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Ogata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiko","family":"Yoshii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuhiro","family":"Goda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhki","family":"Yanase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Hosoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichiro","family":"Ozawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.rmed.2011.09.007","article-title":"The role of mast cells in allergic inflammation","volume":"106","author":"Amin","year":"2012","journal-title":"Respir. 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