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    A natural nephroprotective adjuvant for cancer chemotherapy: Rosmarinic acid disrupts IL-17 A-Ferroptosis coupling in Ifosfamide-induced renal injury
    (Humana Press Inc, 2026) Suzen Celbek, Busra; Simsek, Hasan; Akaras, Nurhan; Kandemir, Ozge; Kizil, Hamit Emre; Mutlu, Huseyin; Kandemir, Fatih Mehmet
    Rosmarinic 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.
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    Multi-Pathway Renoprotection by Betanin Against Docetaxel Nephrotoxicity: Modulation of Inflammation, ER Stress, Apoptosis, and Ferroptosis
    (Wiley, 2026) Celbek, Busra Suzen; Akaras, Nurhan; Simsek, Hasan; Mutlu, Huseyin; Kizil, Hamit Emre; Kandemir, Ozge; Kandemir, Fatih Mehmet
    Docetaxel (DTX), a cornerstone chemotherapeutic agent, has its clinical utility significantly limited by dose-dependent nephrotoxicity. This study investigated the multi-pathway renoprotective mechanisms of betanin (BTN), a natural antioxidant derived from beetroot, against DTX-induced kidney injury. Male Wistar rats received DTX (30 mg/kg, i.p., single dose) with or without BTN (100 mg/kg/day, p.o.) for 7 days. DTX induced severe renal dysfunction with elevated serum urea and creatinine, and significant oxidative stress characterized by increased MDA and decreased GSH, GPx, SOD, and CAT. Molecular analysis demonstrated widespread upregulation of pro-inflammatory (NF-kappa B, TNF-alpha, IL-1 beta), endoplasmic reticulum stress (PERK, ATF6), pro-apoptotic (Caspase-3, Bax, Apaf-1), and pro-ferroptotic (PTGS2, TfR1) mediators, with concurrent downregulation of protective Bcl-2 and GPx4. Histopathological examination revealed extensive tubular injury, while immunohistochemical analysis showed markedly increased kidney injury marker KIM-1 and decreased aquaporin-1 expression. Remarkably, BTN co-administration significantly attenuated all biochemical, molecular, and structural derangements, restored tissue architecture, and normalized KIM-1 and AQP-1 expression. In conclusion, betanin provides robust, multi-pathway renoprotection against docetaxel-induced nephrotoxicity by concurrently targeting oxidative stress, inflammation, ER stress, apoptosis, and ferroptosis.