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Combining single\u2010cell RNA sequencing with functional assays, we identified a novel intercellular communication pathway mediated by Sertoli cell\u2010derived extracellular vesicles (EVs) in Cd\u2010induced testicular injury. In mice, Cd exposure caused testicular atrophy, spermatogenesis disruption, and fibrosis. Multi\u2010omics analyses revealed activation of multiple programmed cell death pathways, including apoptosis, necroptosis, pyroptosis, and ferroptosis. Single\u2010cell RNA sequencing (scRNA\u2010seq) demonstrated testicular cellular remodeling featuring Sertoli cell depletion and fibroblast expansion. Mechanistically, Cd triggered multi\u2010modal programmed cell death (PCD) in Sertoli cells, promoting EV release enriched with damage\u2010associated molecular patterns (DAMPs) and mitochondrial components. These EVs were internalized by testicular macrophages, activating the TLR4\/NF\u2010\u03baB pathway and inducing a pro\u2010inflammatory phenotype. Consequently, activated macrophages stimulated fibroblast\u2010mediated fibrosis via TGF\u2010\u03b2\/Smad signaling. These findings elucidate a Sertoli cell\u2010EV\u2010macrophage\u2010fibroblast axis in Cd\u2010induced testicular damage, offering new insights into environmental toxicant\u2010induced male infertility and potential therapeutic targets.<\/jats:p>","DOI":"10.1002\/advs.202522278","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T20:08:40Z","timestamp":1774469320000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Sertoli Cell\u2010Derived Extracellular Vesicles Orchestrate Cadmium\u2010Induced Testicular Inflammation and Fibrosis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2731-5355","authenticated-orcid":false,"given":"Jianfeng","family":"Ma","sequence":"first","affiliation":[{"name":"Farm Animal Germplasm Resources and Biotech Breeding Key Laboratory of Sichuan Province Sichuan Agricultural University  Chengdu China"},{"name":"State 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