A natural nephroprotective adjuvant for cancer chemotherapy: Rosmarinic acid disrupts IL-17 A-Ferroptosis coupling in Ifosfamide-induced renal injury

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dc.contributor.authorSuzen Celbek, Busra
dc.contributor.authorSimsek, Hasan
dc.contributor.authorAkaras, Nurhan
dc.contributor.authorKandemir, Ozge
dc.contributor.authorKizil, Hamit Emre
dc.contributor.authorMutlu, Huseyin
dc.contributor.authorKandemir, Fatih Mehmet
dc.date.accessioned2026-09-01T15:53:09Z
dc.date.available2026-09-01T15:53:09Z
dc.date.issued2026
dc.departmentBayburt Üniversitesi
dc.description.abstractRosmarinic acid (RA) is a natural polyphenol with established pleiotropic protective effects. Ifosfamide (IFA) is a potent antineoplastic agent whose clinical utility is severely limited by dose-dependent nephrotoxicity, primarily mediated by its metabolite, chloroacetaldehyde (CAA). This study aimed to investigate whether RA protects against IFA-induced nephrotoxicity and to elucidate the underlying molecular mechanisms. Male Wistar albino rats (n = 7 per group) were allocated into four groups: Control, RA-only (50 mg/kg, p.o., 2 days), IFA-only (a single 500 mg/kg, i.p. dose), and IFA + RA. Serum biochemical markers (urea, creatinine), renal oxidative stress parameters (MDA, GSH, SOD, CAT, GPx), gene expression levels (NF-kappa B, TNF-alpha, IL-1 beta, IL-17 A, ACT1, TRAF6, Caspase-3, Bax, Bcl-2, PTGS2, GPX4, TfR1), and histopathological/immunohistochemical analyses (KIM-1, Nephrin, Caspase-3) were performed 24 h post-administration. IFA induced severe renal dysfunction, marked oxidative stress, and extensive histopathological damage. Mechanistically, IFA initiated a pathogenic cascade activating intrinsic apoptosis and ferroptosis, driven by a self-sustaining IL-17 A-TRAF6-NF-kappa B inflammatory loop. RA co-treatment (50 mg/kg) significantly reversed all functional, biochemical, and histological damage by strategically breaking this crosstalk, restoring redox homeostasis, and simultaneously restraining both cell death programs. In conclusion, RA protects against IFA nephrotoxicity by targeting the critical inflammation-ferroptosis coupling, positioning it as a highly promising adjuvant candidate for clinical use to mitigate IFA-induced renal injury.
dc.description.sponsorshipAksaray University -- Open access funding provided by the Scientific and Technological Research Council of Turkiye (TUB & Idot;TAK).
dc.identifier.doi10.1007/s12032-026-03280-z
dc.identifier.issn1357-0560
dc.identifier.issn1559-131X
dc.identifier.issue4
dc.identifier.pmid41795721
dc.identifier.scopus2-s2.0-105032719198
dc.identifier.scopusqualityQ2
dc.identifier.urihttp://dx.doi.org/10.1007/s12032-026-03280-z
dc.identifier.urihttps://hdl.handle.net/20.500.12403/8549
dc.identifier.volume43
dc.identifier.wosWOS:001712384800001
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherHumana Press Inc
dc.relation.ispartofMedical Oncology
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WOS_20260820
dc.subjectAcute Kidney Injury
dc.subjectApoptosis
dc.subjectFerroptosis
dc.subjectIfosfamide
dc.subjectIl-17A
dc.subjectInflammation
dc.subjectNephrotoxicity
dc.subjectOxidative Stress
dc.subjectRosmarinic Acid
dc.titleA natural nephroprotective adjuvant for cancer chemotherapy: Rosmarinic acid disrupts IL-17 A-Ferroptosis coupling in Ifosfamide-induced renal injury
dc.typeArticle

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