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Our recent studies highlighted the key role of histone deacetylase 6 (HDAC6) in the development of PF. To better understand the mechanisms underlying the involvement of HDAC6 in PF, we conducted <jats:italic>in vivo<\/jats:italic> experiments using <jats:italic>Hdac6<\/jats:italic> KO mice and <jats:italic>in vitro<\/jats:italic> studies using human peritoneal mesothelial cells (HPMCs). Our results demonstrated that <jats:italic>HDAC6<\/jats:italic> gene silencing improved PF and angiogenesis <jats:italic>in vivo<\/jats:italic> and altered pathological phenotypes <jats:italic>in vitro<\/jats:italic>. In <jats:italic>Hdac6<\/jats:italic> KO mice, the key pathways regulating extracellular matrix accumulation, angiogenesis, and secretion of inflammatory cytokines (including TGFB1\/SMAD3, HIF\u20101\u03b1\/VEGFR\u20102\/MAPK3\/MAPK1, and TLR4\/NF\u2010\u03baB pathways) were inhibited. We also identified heat shock protein 90 (HSP90) as the substrate of HDAC6 in both PF mice and HPMCs and demonstrated that HDAC6 exerted its regulatory function in PF through the deacetylation of HSP90. Overall, our study provides novel insights into the critical role of the HDAC6\u2010HSP90 interplay in PF using <jats:italic>Hdac6<\/jats:italic> KO mice. We identify HSP90 as an essential substrate through which HDAC6 exerts its function in PF, providing an experimental basis for the development of novel therapeutic strategies. \u00a9 2025 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6436","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T09:09:55Z","timestamp":1750410595000},"page":"447-464","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Genetic deletion of histone deacetylase 6 prevents peritoneal fibrosis via suppression of heat shock protein 90 deacetylation"],"prefix":"10.1002","volume":"266","author":[{"given":"Yingfeng","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Nephrology, Shanghai East Hospital Tongji University School of Medicine  Shanghai PR 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