Hesperidin mitigates DEHP-induced nephrotoxicity through anti-oxidant, anti-apoptotic, and anti-inflammatory pathway modulation: Evidence from Nrf2/HO-1/Keap-1, Bax/Bcl-2/Caspase-3, and TLR4/NF-κB axis activatione

Articles in Press

Document Type : Review Article

Authors

1 Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey

2 Department of Animal Breeding and Husbandry, Faculty of Veterinary Medicine, Atatürk University, Erzurum,Turkey

10.22038/ijbms.2026.89049.19222

Abstract

Objective(s): This study aimed to assess the protective role of hesperidin (HSP), a citrus flavonoid, against di-(2-ethylhexyl) phthalate (DEHP)-induced kidney toxicity in rats, focusing on oxidative stress, apoptosis, inflammation, and anti-oxidant defense pathways.
Materials and Methods: Thirty-five male rats were randomly assigned into five groups (7 per group):  control group, DEHP-treated group (1 g/kg), DEHP + HSP (100 mg/kg) group, DEHP + HSP (200 mg/kg) group, and HSP-alone group, and treated orally for 10 consecutive days.  Kidney tissues were collected for biochemical assays, including malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Gene expression of Nrf2, Keap1, HO-1, Bax, Bcl-2, Caspase-3, TLR-4, and NF-κB was analyzed using real-time PCR, and protein levels were evaluated using Western blotting.
Results: DEHP significantly increased oxidative damage and the expression of inflammatory and apoptotic markers, while decreasing anti-oxidant parameters. Co-treatment with HSP, particularly at 200 mg/kg, restored anti-oxidant balance, reduced lipid peroxidation, and down-regulated the expression of TLR-4, NF-κB, and Caspase-3. Moreover, HSP increased Bcl-2 levels and enhanced Nrf2/HO-1 signaling, as confirmed by both gene and protein expression data.
Conclusion: HSP demonstrates dose-dependent renoprotective effects against DEHP-induced nephrotoxicity in rats. The protective mechanism involves anti-oxidant enhancement and inhibition of oxidative stress-induced inflammation and apoptosis, supporting the therapeutic potential of HSP in managing phthalate-related renal injury.

Keywords

Main Subjects

References

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Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 02 May 2026

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