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The underlying regulatory mechanism remains unclear. Using human lens epithelial cell lines and the ex vivo cultured rat lens capsular bag model, we found that the lens epithelial cells secrete HSP90\u03b1 extracellularly (eHSP90) through an autophagy\u2010associated pathway. Administration of recombinant GST\u2010HSP90\u03b1 protein or its M\u2010domain induces the elongation of rat CRLEC cells with concomitant upregulation of the crucial fiber cell transcriptional factor PROX1and its downstream targets, \u03b2\u2010 and \u03b3\u2010crystallins and structure proteins. This regulation is abolished by PROX1 siRNA. GST\u2010HSP90\u03b1 upregulates PROX1 by binding to LRP1 and activating LRP1\u2010AKT mediated YAP degradation. The upregulation of GST\u2010HSP90\u03b1 on PROX1 expression and CRLEC cell elongation is inhibited by LRP1 and AKT inhibitors, but activated by YAP\u20101 inhibitor (VP). These data demonstrated that the capsular residue epithelial cells upregulate and secrete eHSP90\u03b1, which in turn drive the differentiation of lens epithelial cell to fiber cells. The recombinant HSP90\u03b1 protein is a potential novel differentiation regulator during lens regeneration.<\/jats:p>","DOI":"10.1096\/fj.202201187rr","type":"journal-article","created":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T05:41:27Z","timestamp":1674798087000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Extracellular\n                    <scp>HSP90<\/scp>\n                    promotes differentiation of lens epithelial cells to fiber cells by activating\n                    <scp>LRP1\u2010YAP\u2010PROX1<\/scp>\n                    axis"],"prefix":"10.1096","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9774-801X","authenticated-orcid":false,"given":"Jing","family":"Li","sequence":"first","affiliation":[{"name":"Joint National Laboratory for Antibody Drug Engineering The First Affiliated Hospital of Henan University, Henan University  Kaifeng China"},{"name":"Kaifeng Key Lab for 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