{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T04:07:14Z","timestamp":1792296434243,"version":"4.4.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T00:00:00Z","timestamp":1704931200000},"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:sec><jats:title>Background<\/jats:title><jats:p>Heat shock protein 90 (HSP90) is an important chaperone supporting the function of many proinflammatory client proteins. Recent studies indicate HSP90 inhibition may be a novel mechanism of action for inflammatory skin diseases; however, this has not been explored in atopic dermatitis (AD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Our study aimed to investigate HSP90 as a novel target to treat AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Experimental models of AD were used including primary human keratinocytes stimulated with cytokines (TNF\/IFN\u03b3 or TNF\/IL-4) and a mouse model established by MC903 applications.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In primary human keratinocytes using RT-qPCR, the HSP90 inhibitor RGRN-305 strongly suppressed the gene expression of Th1- (<jats:italic>TNF<\/jats:italic>, <jats:italic>IL1B<\/jats:italic>, <jats:italic>IL6<\/jats:italic>) and Th2-associated (<jats:italic>CCL17<\/jats:italic>, <jats:italic>CCL22, TSLP)<\/jats:italic> cytokines and chemokines related to AD. We next demonstrated that topical and oral RGRN-305 robustly suppressed MC903-induced AD-like inflammation in mice by reducing clinical signs of dermatitis (oedema and erythema) and immune cell infiltration into the skin (T cells, neutrophils, mast cells). Interestingly, topical RGRN-305 exhibited similar or slightly inferior efficacy but less weight loss compared with topical dexamethasone. Furthermore, RNA sequencing of skin biopsies revealed that RGRN-305 attenuated MC903-induced transcriptome alterations, suppressing genes implicated in inflammation including AD-associated cytokines (<jats:italic>Il1b, Il4, Il6, Il13<\/jats:italic>), which was confirmed by RT-qPCR. Lastly, we discovered using Western blot that RGRN-305 disrupted JAK-STAT signaling by suppressing the activity of STAT3 and STAT6 in primary human keratinocytes, which was consistent with enrichment analyses from the mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>HSP90 inhibition by RGRN-305 robustly suppressed inflammation in experimental models mimicking AD, proving that HSP90 inhibition may be a novel mechanism of action in treating AD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1289788","type":"journal-article","created":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T04:33:58Z","timestamp":1704947638000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Heat shock protein 90 inhibition attenuates inflammation in models of atopic dermatitis: a novel mechanism of action"],"prefix":"10.3389","volume":"14","author":[{"given":"Hakim","family":"Ben 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