{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:10:11Z","timestamp":1790014211245,"version":"4.0.1"},"reference-count":65,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Cyclophosphamide (CTX) is a widely used chemotherapeutic agent with well-established efficacy; however, its clinical use is limited by dose-dependent adverse effects, particularly nephrotoxicity. Protodioscin (Prot), a bioactive saponin derived from plants of the Dioscoreaceae family, has demonstrated notable antioxidant and anti-inflammatory properties. This study aimed to evaluate the protective effects of Prot against CTX-induced cytotoxicity in HEK-293 cells. Primary HEK-293 kidney cells were exposed to the IC50 concentration of CTX in the presence or absence of Prot (5 and 10 \u00b5M) for 24 hours. Cell viability was assessed using the MTT assay. Gene expression of Bax and Bcl-2 was measured by real-time PCR assay, while protein expression of Bax, cleaved caspase-3, Bcl-2, ATF6, PERK, GRP78, CHOP, p-eIF2\u03b1, p-PERK, and cleaved ATF6 were evaluated by Western blot analysis. Oxidative stress parameters, including CAT, SOD, GPx, GSH, MDA, and NO, were quantified using spectrophotometric assays, and kidney injury markers (KIM-1 and cystatin C) were measured by ELISA. Prot decreased Bax and caspase 3 expression and increased Bcl-2 expression in HEK-293 cells exposed to CTX, which was accompanied by reduced apoptosis. Treatment with 5 and 10 \u00b5M Prot significantly reduced the expression of ATF6, PERK, GRP78, CHOP, p-eIF2\u03b1, p-PERK and Cleaved- ATF6 proteins in CTX-exposed HEK-293 cells. Additionally, treatment with Prot significantly increased catalase, GPx, GSH, and SOD levels, while reducing KIM-1, cystatin C, MDA, and NO levels in HEK-293 cells subjected to CTX. These findings suggest that Prot exerts a protective role against CTX-induced renal injury in HEK-293 cells by modulating apoptotic pathways, attenuating endoplasmic reticulum stress, and improving antioxidant indices.<\/jats:p>","DOI":"10.1371\/journal.pone.0357227","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T17:33:13Z","timestamp":1790011993000},"page":"e0357227","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protodioscin mitigates cyclophosphamide-induced renal toxicity in HEK-293 cells by regulating endoplasmic reticulum stress, antioxidant defense, and apoptotic pathways"],"prefix":"10.1371","volume":"21","author":[{"given":"Ahmad Reza","family":"Ahmadi","sequence":"first","affiliation":[{"name":"Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences","place":["Kermanshah, Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Touraj","family":"Zamir Nasta","sequence":"additional","affiliation":[{"name":"Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences","place":["Ahvaz, Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ardeshir","family":"Abbasi","sequence":"additional","affiliation":[{"name":"Factually of Medical Sciences, Tarbiat Modares University","place":["Tehran, Iran"],"department":["Department of Immunology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Reza","family":"Tabandeh","sequence":"additional","affiliation":[{"name":"Shahid Chamran University of Ahvaz","place":["Ahvaz, Iran"],"department":["Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine"]},{"name":"Stem Cells and Transgenic Technology Research Center, Shahid Chamran University of Ahvaz","place":["Ahvaz, Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5097-7974","authenticated-orcid":true,"given":"Cyrus","family":"Jalili","sequence":"additional","affiliation":[{"name":"Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences","place":["Kermanshah, Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"issue":"18","key":"pone.0357227.ref001","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1200\/JCO.20.03502","article-title":"National Marrow Donor Program-Sponsored Multicenter, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation Using Post-Transplant Cyclophosphamide","volume":"39","author":"BE Shaw","year":"2021","journal-title":"J Clin Oncol"},{"issue":"3","key":"pone.0357227.ref002","doi-asserted-by":"crossref","first-page":"231","DOI":"10.2217\/fon-2018-0597","article-title":"ATLANTIS: a Phase III study of lurbinectedin\/doxorubicin versus topotecan or cyclophosphamide\/doxorubicin\/vincristine in patients with small-cell lung cancer who have failed one prior platinum-containing line","volume":"15","author":"AF Farago","year":"2019","journal-title":"Future Oncol"},{"key":"pone.0357227.ref003","doi-asserted-by":"crossref","first-page":"107580","DOI":"10.1016\/j.fbio.2025.107580","article-title":"Multiomics analysis revealed the immune-enhancement effects of xylooligosaccharides on cyclophosphamide-induced immunosuppression","volume":"73","author":"M He","year":"2025","journal-title":"Food Bioscience"},{"key":"pone.0357227.ref004","doi-asserted-by":"crossref","first-page":"543531","DOI":"10.4061\/2010\/543531","article-title":"DNA damage induced by alkylating agents and repair pathways","volume":"2010","author":"N Kondo","year":"2010","journal-title":"J Nucleic Acids"},{"issue":"6","key":"pone.0357227.ref005","first-page":"711","article-title":"Toxic Effects of Different Doses of Cyclophosphamide on Liver and Kidney Tissue in Swiss Albino Mice: A Histopathological Study","volume":"28","author":"N Bhat","year":"2018","journal-title":"Ethiop J Health Sci"},{"key":"pone.0357227.ref006","doi-asserted-by":"crossref","unstructured":"\u00c7aydere M, Jafarzade A, \u00c7a\u011flayan FB, Anadol E, Burgucu D, Y\u0131lmaz C. 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