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Focal segmental glomerulosclerosis (FSGS) remains a clinical challenge in terms of treatment. To investigate the role of the P2X7R-NLRP3 inflammasome pathway in podocyte injury in PNS, focusing on its regulation of CXCL16 in FSGS. Clinical renal tissues from children with PNS were analyzed by immunohistochemistry for P2X7R, NLRP3, and CXCL16 expression. In vitro, adriamycin (ADR)-induced podocyte injury models were established, with P2X7R knockdown via lentiviral transduction. Protein and mRNA levels of pathway components and injury markers were assessed by Western Blot and RT-qPCR; IL-1\u03b2 and IL-18 were measured by ELISA. In vivo, ADR nephropathy was induced with ADR 25\u00a0mg\/kg by a single tail vein injection in NLRP3-knockout and wild-type male mice (n\u2009=\u200910 per group C57BL\/6J, 5\u00a0weeks old). Serum albumin, total cholesterol, 24\u00a0h urine protein, renal expression of CXCL16, Nephrin, and inflammatory cytokines, and podocyte ultrastructure were evaluated. Glomerular P2X7R, NLRP3, and CXCL16 were significantly upregulated in PNS patients, particularly in FSGS versus MCD. ADR-induced podocytes showed increased expression of these markers and inflammatory cytokines, which P2X7R knockdown reversed. NLRP3 knockout in mice attenuated ADR nephropathy, improving biochemical parameters, reducing proteinuria, downregulating CXCL16 and inflammatory factors, restoring Nephrin, and ameliorating podocyte ultrastructural injury. The P2X7R-NLRP3 inflammasome pathway promotes podocyte injury in PNS via CXCL16 upregulation, revealing novel mechanistic insights and potential therapeutic targets.<\/jats:p>","DOI":"10.1038\/s41598-026-47345-5","type":"journal-article","created":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T05:44:23Z","timestamp":1775367863000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibiting the P2X7R-NLRP3 inflammasome pathway regulates CXCL16 to alleviate podocyte injury in mice with adriamycin nephropathy"],"prefix":"10.1038","volume":"16","author":[{"given":"Yanji","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Zong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suwen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhui","family":"Zhen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuzhen","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,5]]},"reference":[{"issue":"2","key":"47345_CR1","first-page":"199","volume":"45","author":"OP Mishra","year":"2023","unstructured":"Mishra, O. 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