Ameliorative Effects of Geraniol on Cyclophosphamide-Induced Nephrotoxicity: Evidence from Nuclear Factor Erythroid 2-related Factor 2 (Nrf-2) Activation and Apoptosis Modulation
Objective: The cyclophosphamide (CP)-related nephrotoxicity may impede cancer treatment. This study investigated the efficacy of geraniol (Ge) at two doses against CP nephrotoxicity.
Methods: Fourty-two Wistar albino rats were allocated into six groups (n=7 each group): Group I, control; Group II, CP; Group III, CP+Ge 100 mg/kg; Group IV, CP+Ge 200 mg/kg; Group V, Ge 100 mg/kg; and Group VI, Ge 200 mg/kg. At the end of study, alterations in renal tissues were evaluated using hematoxylin-eosin and histopathological scores were determined. Masson’s trichrome and Periodic acid–Schiff (PAS) staining were also performed for evaluation of fibrosis, parietal layer of Bowman capsule, and Bowman’s space. Immunofluorescence analysis assessed oxidative stress and apoptosis. Consequently, the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf-2), caspase 3, and caspase 9 were evaluated.
Results: CP caused the histopathological changes, including tubular damage, glomerular degeneration, interstitial inflammation. Ge restored the increased histopathological scores, parietal layer of Bowman capsule, and Bowman’s space caused by CP without dose dependence (P<0.001 for both dose). CP decreased the expression of Nrf-2, while Ge improved this disturbance with greater efficacy at a higher dose (P<0.001 for all). CP exposure increased both caspase 3 and caspase 9 (P<0.001 for both). Ge decreased the expressions of caspase 3 and caspase 9 at two doses (P<0.001 for all). In addition, Ge was more effective in repairing caspase 3 at a higher dose (P=0.006).
Conclusion: Ge seems to effectively reverse CP-induced nephrotoxicity. The histopathological improvements are mediated by mechanisms involving the attenuation of oxidative stress and apoptosis. The efficacy of Ge is also dose-dependent.
1. Ayza MA, Zewdie KA, Yigzaw EF, et al. Potential Protective Effects of Antioxidants against Cyclophosphamide-Induced Nephrotoxicity. Int J Nephrol. 2022;2022:5096825. doi:10.1155/2022/5096825.
2. Oberiukhtin D, Chernitskiy A, Hu D, Sarapultsev A. Cyclophosphamide-Induced Nephrotoxicity and Nephroprotection in Rodent Models: A Systematic Review and Random-Effects Meta-Analysis (2010–2025). J Xenobiotics. 2026;16(2):48. doi:10.3390/jox16020048.
3. Wu Q, Wang X, Nepovimova E, Wang Y, Yang H, Kuca K. Mechanism of cyclosporine A nephrotoxicity: Oxidative stress, autophagy, and signalings. Food Chem Toxicol. 2018;118:889–907. doi:10.1016/j.fct.2018.06.054.
4. Ranasinghe R, Mathai M, Zulli A. Cytoprotective remedies for ameliorating nephrotoxicity induced by renal oxidative stress. Life Sci. 2023;318:121466. doi:10.1016/j.lfs.2023.121466.
5. Dong W, Wan J, Yu H, et al. Nrf2 protects against methamphetamine-induced nephrotoxicity by mitigating oxidative stress and autophagy in mice. Toxicol Lett. 2023;384:136–148. doi:10.1016/j.toxlet.2023.08.002.
6. Caglayan C, Temel Y, Kandemir FM, Yildirim S, Kucukler S. Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. Environ Sci Pollut Res. 2018;25(21):20968–20984. doi:10.1007/s11356-018-2242-5.
7. Ijaz MU, Mustafa S, Batool R, Naz H, Ahmed H, Anwar H. Ameliorative effect of herbacetin against cyclophosphamide-induced nephrotoxicity in rats via attenuation of oxidative stress, inflammation, apoptosis and mitochondrial dysfunction. Hum Exp Toxicol. 2022;41:9603271221132140. doi:10.1177/09603271221132140.
8. Alasmari AF, Ali N, Alharbi M, et al. Geraniol Ameliorates Doxorubicin-Mediated Kidney Injury through Alteration of Antioxidant Status, Inflammation, and Apoptosis: Potential Roles of NF-κB and Nrf2/Ho-1. Nutrients. 2022;14(8):1620. doi:10.3390/NU14081620.
9. Mahmoud NM, Elshazly SM, Rezq S. Geraniol protects against cyclosporine A-induced renal injury in rats: Role of Wnt/β-catenin and PPARγ signaling pathways. Life Sci. 2022;291:120259. doi:10.1016/j.lfs.2021.120259.
10. Cuce G, Esen HH, Koc T, et al. Vitamin E partially ameliorates cyclophosphamide-induced nephrotoxicity in rats. Prog Nutr. 2016;18(2):140–145.
11. Mohamed ME, Elmorsy MA, Younis NS. Renal Ischemia/Reperfusion Mitigation via Geraniol: The Role of Nrf-2/HO-1/NQO-1 and TLR2,4/MYD88/NFκB Pathway. Antioxidants (Basel). 2022;11(8):1568. doi:10.3390/antiox11081568.
12. Canbaz HT, Sozen ME, Cinar Ayan I, et al. Effects of Carvacrol on Oxidative Stress and Fibrosis in Streptozotocin-Induced Diabetic Nephropathy: Histological, Gene Expression, and Biochemical Insights. Int J Mol Sci. 2025;27(1):291. doi:10.3390/ijms27010291.
13. Gültekin B, Çetinkaya Karabekir S, Çınar Ayan İ, Basri Savaş H, Kalkan S. Protective role of astaxanthin against bisphenol A induced biochemical and histopathological alterations in rat kidneys. Iran J Basic Med Sci. 2025;28(12):1647–1655. doi:10.22038/ijbms.2025.88356.19081.
14. Mombeini MA, Kalantar H, Sadeghi E, Goudarzi M, Khalili H, Kalantar M. Protective effects of berberine as a natural antioxidant and anti-inflammatory agent against nephrotoxicity induced by cyclophosphamide in mice. Naunyn Schmiedebergs Arch Pharmacol. 2022;395(2):187–194. doi:10.1007/s00210-021-02182-3.
15. Wanas H, El-Shabrawy M, Mishriki A, Attia H, Emam M, Aboulhoda BE. Nebivolol protects against cyclophosphamide-induced nephrotoxicity through modulation of oxidative stress, inflammation, and apoptosis. Clin Exp Pharmacol Physiol. 2021;48(5):811–819. doi:10.1111/1440-1681.13481.
16. Salama RM, Nasr MM, Abdelhakeem JI, Roshdy OK, ElGamal MA. Alogliptin attenuates cyclophosphamide-induced nephrotoxicity: a novel therapeutic approach through modulating MAP3K/JNK/SMAD3 signaling cascade. Drug Chem Toxicol. 2022;45(3):1254–1263. doi:10.1080/01480545.2020.1814319.
17. Temel Y, Kucukler S, Yıldırım S, Caglayan C, Kandemir FM. Protective effect of chrysin on cyclophosphamide-induced hepatotoxicity and nephrotoxicity via the inhibition of oxidative stress, inflammation, and apoptosis. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(3):325–337. doi:10.1007/s00210-019-01741-z.
18. Dil E, Topcu A, Mercantepe T, et al. Agomelatine on cisplatin-induced nephrotoxicity via oxidative stress and apoptosis. Naunyn Schmiedebergs Arch Pharmacol. 2023;396(10):2753–2764. doi:10.1007/s00210-023-02632-0.
19. Uyumlu AB, Satılmış B, Atıcı B, Taşlıdere A. Phenethyl isothiocyanate protects against cyclophosphamide-induced nephrotoxicity via nuclear factor E2–related factor 2 pathway in rats. Exp Biol Med (Maywood). 2023;248(2):157–164. doi:10.1177/15353702221139206.
20. Sinanoglu O, Yener AN, Ekici S, Midi A, Aksungar FB. The protective effects of spirulina in cyclophosphamide induced nephrotoxicity and urotoxicity in rats. Urology. 2012;80(6):1392.e1-1392.e6. doi:10.1016/j.urology.2012.06.053.
21. Fouad AA, Qutub HO, Al-Melhim WN. Punicalagin alleviates hepatotoxicity in rats challenged with cyclophosphamide. Environ Toxicol Pharmacol. 2016;45:158–162. doi:10.1016/j.etap.2016.05.031.
22. Sozen ME, Savas HB, Cuce G. Protective Effects of Selenium against Acrylamide-Induced Hepatotoxicity in Rats. Pak Vet J. 2024;44(2):274–279. doi:10.29261/pakvetj/2024.153.
23. Kannan K, Jain SK. Oxidative stress and apoptosis. Pathophysiology. 2000;7(3):153–163. doi:10.1016/s0928-4680(00)00053-5.
24. Karabekir SC, Sozen ME, Ayan IC, Savas HB, Cuce G, Kalkan S. The ameliorative effects of hesperidin in rats developed hepatotoxicity with deltamethrin. Iran J Basic Med Sci. 2025;28(7):929–936. doi:10.22038/ijbms.2025.82598.17854.
25. Asadi M, Taghizadeh S, Kaviani E, et al. Caspase-3: Structure, function, and biotechnological aspects. Biotechnol Appl Biochem. 2022;69(4):1633–1645. doi:10.1002/bab.2233.
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Article Information
- Article Type Research Article
- Submitted April 28, 2026
- Accepted May 31, 2026
- Published August 1, 2026
- Issue Forthcoming Issue: Vol. 12 Iss. 8 (August 2026)
- Section Research Article
- Categories
All data generated or analyzed during this study are included in this published article. The data that support the findings of this study are available on request from the corresponding author, upon reasonable request
