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Increasing evidence indicates that extracellular vesicles (EVs) contribute to pathogenic signal dissemination in lysosomal storage disorders. We hypothesized that EVs released from AFD-affected cells transfer toxic metabolites and molecular cues to recipient cells, thereby amplifying disease mechanisms. As a proof-of-concept study, urinary EVs were isolated from adults with AFD and healthy controls by ultracentrifugation and characterized by flow cytometry. Renal immortalized cells (HEK293) were treated with either healthy or AFD EVs to assess Gb3 accumulation, \u03b1-galactosidase A activity, and autophagic markers (Beclin-1, LC3 II\/LC3-I ratio, and p62) at multiple time points. HEK293 cells exposed for 24\u00a0h to urinary EVs from 10 AFD patients showed Gb3 accumulation comparable to that observed in urinary epithelial cells from AFD subjects, along with increased \u03b1-galactosidase A activity relative to untreated and control-EV\u2013treated cells. This was accompanied by impairment of autophagic flux as indicated by elevated LC3B-II\/LC3-I ratios and accumulation of the autophagy substrate p62 after 72\u00a0h of exposure to AFD EVs. Autophagic inhibition was further supported by a significant reduction of Beclin-1 at 24\u201372\u00a0h in cells exposed to AFD EVs and increased Bcl-2 expression, a negative regulator of Beclin-1. These findings provide new insight into the potential involvement of EVs in AFD pathogenesis, suggesting that systemic manifestations may arise, at least in part, from EV-mediated transfer of pathogenic lipids and signaling molecules to recipient cells.<\/jats:p>","DOI":"10.1042\/cs20250868","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T13:40:47Z","timestamp":1774359647000},"page":"651-662","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Extracellular vesicles as novel mediators of pathology in Anderson\u2013Fabry disease"],"prefix":"10.1042","volume":"140","author":[{"given":"Anna\u00a0Olena","family":"Kalmykova","sequence":"first","affiliation":[{"name":"1Division of Metabolic Diseases, Department of Medicine, Padova University Hospital, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1839-1404","authenticated-orcid":false,"given":"Maria\u00a0Lina","family":"Massimino","sequence":"additional","affiliation":[{"name":"2Neuroscience Institute, National Research Council (CNR), Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Vettore","sequence":"additional","affiliation":[{"name":"1Division of Metabolic Diseases, Department of Medicine, Padova University Hospital, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3557-8078","authenticated-orcid":false,"given":"Giorgia","family":"Gugelmo","sequence":"additional","affiliation":[{"name":"1Division of Metabolic Diseases, Department of Medicine, Padova University Hospital, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianni","family":"Carraro","sequence":"additional","affiliation":[{"name":"3Nephrology, Dialysis and Transplant Unit, Department of Medicine, Padova University Hospital, University of Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0574-4052","authenticated-orcid":false,"given":"Laura","family":"De Michieli","sequence":"additional","affiliation":[{"name":"4Department of Cardio-Thoraco-Vascular Sciences and Public Health, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6510-2097","authenticated-orcid":false,"given":"Gian\u00a0Paolo","family":"Fadini","sequence":"additional","affiliation":[{"name":"1Division of Metabolic Diseases, Department of Medicine, Padova University Hospital, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1202-0191","authenticated-orcid":false,"given":"Alessandro","family":"Bertoli","sequence":"additional","affiliation":[{"name":"2Neuroscience Institute, National Research Council (CNR), Padova, Italy"},{"name":"5Department of Biomedical Sciences, University of Padova, Padova, Italy"},{"name":"6Padova Neuroscience Center, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5147-4367","authenticated-orcid":false,"given":"Nicola","family":"Vitturi","sequence":"additional","affiliation":[{"name":"1Division of Metabolic Diseases, Department of Medicine, Padova University Hospital, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6146-3015","authenticated-orcid":false,"given":"Livia","family":"Lenzini","sequence":"additional","affiliation":[{"name":"7Department of Medicine, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"2026041705464955100_B1","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/B978-1-4557-4617-0.00044-3","article-title":"Fabry disease","author":"Sunder-Plassmann","year":"2014","journal-title":"Natl. 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