Erythropoietin and Ferulic Acid Loaded on Fe3O4 Nanoparticles Exert Therapeutic Effect against Acute Kidney Injury Induced by Cisplatin Via Bcl-2/Bax, IL-6, TGF-β, and GPX-4 Mechanisms

Abstract

Background: Acute kidney damage occurs in 30%–46% of patients receiving cisplatin chemotherapy; nevertheless, effective preventive and treatment strategies are insufficient. Ferulic acid, despite its potent antioxidant and anti-inflammatory properties, exhibits from poor aqueous solubility, rapid metabolism, and low bioavailability, which significantly limit its therapeutic efficiency in vivo when administered in its free form. Therefore, an effective delivery system was required to overcome these limitations, enhance FA stability, and prolong its biological residence time in renal tissue. Fe₃O₄ nanoparticles provided an appropriate solution to this challenge by coating it to a core-shell system of Fe₃O₄@C nanoparticles, which were selected not only as a carrier but also to enhance FA delivery, maintaining its therapeutic activity, and providing superior nephroprotection. Objectives: The present research demonstrates the therapeutic efficacy of Erythropoietin (EPO), magnetic nanoparticles (Fe3O4-NPs), Ferulic acid (FA), and FA-loaded Fe3O4-NPs@C against AKI induced by cisplatin. Methods: Forty-two rats were divided into seven groups (n = 6). Normal control, cisplatin (6 mg/kg), cisplatin + EPO (1000 IU/kg, intraperitoneally), cisplatin + FA (50 mg/kg, orally), cisplatin + Fe3O4-NPs (5 mg/kg, intraperitoneally), combination group (cisplatin, EPO, FA, and Fe3O4-NPs), and cisplatin + FA/Fe3O4-NPs@C (5 mg/kg, intraperitoneally). Euthanisation occurred after 7 days of administration. Results: Cisplatin-induced nephrotoxicity significantly elevated renal markers compared to the normal group (p ≤ 0.05), with creatinine reaching 0.93 mg/dL and urea 116.88 mg/dL. Treatment with ferulic acid (FA), Fe3O4-NPs, and erythropoietin (EPO) reduced these levels. At the same time, their combination and FA/Fe3O4-NPs@C further significantly decreased creatinine and urea levels (p ≤ 0.05), thereby restoring renal function and elevating antioxidants (catalase, glutathione reductase, superoxide dismutase). Notably, GPX-4 levels markedly increased (p ≤ 0.05) in the FA/Fe3O4-NPs@C group, confirming ferroptosis inhibition via upregulated ferritin and GSH; Bcl-2 expression rose while Bax declined (p ≤ 0.05), indicating anti-apoptotic effects. These biochemical changes were corroborated by histopathological and immunohistochemical findings, with reduced inflammation (downregulated IL-6) and fibrosis (downregulated TGF-β). Conclusion: FA/Fe3O4-NPs@C protects against nephrotoxicity of cisplatin by restoring renal antioxidant defenses, inhibiting inflammation, ferroptosis, and apoptosis, thereby enhancing renal function and recovery.