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<p>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 <i>Wistar albino</i> rats (<i>n</i> = 7 per group) were allocated into four groups: Control, RA-only (50&#xa0;mg/kg, p.o., 2 days), IFA-only (a single 500&#xa0;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-κB, TNF-α, IL-1β, IL-17&#xa0;A, ACT1, TRAF6, Caspase-3, Bax, Bcl-2, PTGS2, GPX4, TfR1), and histopathological/immunohistochemical analyses (KIM-1, Nephrin, Caspase-3) were performed 24&#xa0;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&#xa0;A-TRAF6-NF-κB inflammatory loop. RA co-treatment (50&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月8日

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  • Büşra Süzen Celbek,
  • Hasan Şimşek,
  • Nurhan Akaras,
  • Özge Kandemir,
  • Hamit Emre Kızıl,
  • Hüseyin Mutlu,
  • Fatih Mehmet Kandemir

摘要

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-κB, TNF-α, IL-1β, 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-κB 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.