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This study reveals how heat shock transcription factor 4 (HSF4) deficiency regulates SEV secretion in lens epithelial cells through chaperone\u2010mediated autophagy (CMA). Compared to mLEC\/HA\u2010Hsf4b cells, SEVs secreted by HSF4\u2010deficient mLEC\/Hsf4<jats:sup>\u2212\/\u2212<\/jats:sup> cells showed significantly increased levels of CMA\u2010related proteins (HSP70, HSC70, LAMP2A, and HSP90) and EGFR, while LC3 II levels were reduced. Additionally, EGFR\u2010enriched SEVs activated downstream ERK\/AKT signaling pathways, promoting the proliferation and migration of lens epithelial cells and inducing epithelial\u2013mesenchymal transition (EMT). Further inhibition experiments showed that blocking HSP70 and HSP90 with apoptozole and retaspimycin, or silencing LAMP2A with siRNA, reduced SEV secretion in HSF4\u2010deficient cells. Collectively, enhanced CMA activity and increased SEV secretion induced by HSF4 deficiency may represent a potential mechanism underlying congenital cataract development.<\/jats:p>","DOI":"10.1002\/jcb.70031","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T06:48:13Z","timestamp":1744354093000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Deficiency of HSF4 Increases the Secretion of Small Extracellular Vesicles via Upregulation of Chaperone\u2010Mediated Autophagy"],"prefix":"10.1002","volume":"126","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8790-1373","authenticated-orcid":false,"given":"Jingjing","family":"Liu","sequence":"first","affiliation":[{"name":"Laboratory of Ophthalmology and Vision Science, Department of Ophthalmology The First Affiliated Hospital of Zhengzhou University Zhengzhou 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