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Patients with sepsis-related ARDS had reduced levels of HSP90AA1. However, whether the changes in CD8<jats:sup>+<\/jats:sup> T cells were related to HSP90\u03b1, encoded by the HSP90AA1 gene, was unclear. This study aimed to examine the regulatory mechanism of HSP90\u03b1 and its impact on CD8<jats:sup>+<\/jats:sup> T-cell exhaustion in lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, by conducting a mouse model of ALI, we found that one week after LPS-induced ALI, CD8<jats:sup>+<\/jats:sup> T cells showed exhaustion characteristics. At this time, proliferation and cytokine release in CD8<jats:sup>+<\/jats:sup> T cells were reduced. The inhibitory costimulatory factors PD-1 and Tim-3, on the other hand, were enhanced. Meanwhile, the expression of HSP90\u03b1 and STAT1 decreased significantly. The in vitro studies showed that HSP90\u03b1 stimulation or inhibition affected the CD8<jats:sup>+<\/jats:sup> T-cell exhaustion phenotype. Interference with STAT1 reduced the expression of HSP90\u03b1 and impaired its regulation of CD8<jats:sup>+<\/jats:sup> T cells. The Co-Immunoprecipitation results indicated that HSP90\u03b1 can directly or indirectly bind to TOX to regulate TOX expression and downstream signal transduction. In summary, by inhibiting TOX-mediated exhaustion signaling pathways, HSP90\u03b1 inhibited CD8<jats:sup>+<\/jats:sup> T-cell exhaustion in ALI. The participation of STAT1 in the regulation of HSP90\u03b1 was required.<\/jats:p>","DOI":"10.1038\/s41420-024-02046-8","type":"journal-article","created":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T08:02:10Z","timestamp":1718265730000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Heat shock protein 90\u03b1 reduces CD8+ T cell exhaustion in acute lung injury induced by lipopolysaccharide"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4669-8905","authenticated-orcid":false,"given":"Lei","family":"Yan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4863-1130","authenticated-orcid":false,"given":"Yi","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7095-9696","authenticated-orcid":false,"given":"Chaoyang","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,13]]},"reference":[{"key":"2046_CR1","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1001\/jama.2016.0287","volume":"315","author":"M Singer","year":"2016","unstructured":"Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. 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