The Effect of Apigenin as an Antioxidant in the Kidney Rats Induced by Excess Iron-Dextran

Salsabila Raniah; Ari Estuningtyas; Rani Wardani Hakim

doi:10.24036/eksakta/vol27-iss06/715

EKSAKTA: Berkala Ilmiah Bidang MIPA

Open Access

The Effect of Apigenin as an Antioxidant in the Kidney Rats Induced by Excess Iron-Dextran

Salsabila Raniah ¹

, Ari Estuningtyas ²

, Rani Wardani Hakim ³

¹ Master’s Programme in Biomedical Science, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

² Department of Pharmacology and Therapeutic, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

³ Department of Medical Pharmacy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

Published 2026-11-14

Vol. 27 No. 06 (2026) PAGES 1099-1110

DOI 10.24036/eksakta/vol27-iss06/715

Views / Downloads 0 0

Download PDF

Abstract

Excess renal iron may generate reactive oxygen species, which may deplete antioxidant systems. Apigenin may limit renal iron accumulation and support antioxidant defenses. This study evaluated apigenin in rats given excess iron. Sprague-Dawley rats were randomized into normal (N), iron overload (IO), deferiprone, and apigenin (25, 50, and 100 mg/kg BW) groups (n = 4/group). Iron dextran (15 mg/250 g BW) was administered for four weeks and continued four more weeks with treatment. Renal iron and GSH were measured. Renal iron in the IO group increased 3.18-fold compared with the N group (504.8 vs. 158.8 mg/kg; p < 0.05). Deferiprone numerically lowered renal iron by 21.69% (395.3 mg/kg) compared with IO (p > 0.05). None of the apigenin doses significantly reduced renal iron (644.5, 579.8, and 699.5 mg/kg) or increased GSH (39.3, 43.3, and 36.0 nmol/g) compared with IO (504.8 mg/kg and 43.5 nmol/g; p > 0.05), whereas GSH was numerically higher in deferiprone than in IO (49.5 nmol/g; p > 0.05). Renal GSH in the apigenin 100 mg/kg BW group was significantly lower than deferiprone (p < 0.05). Overall, apigenin was not shown to significantly reduce renal iron or increase GSH.

References

1

[1] Obeagu, E. I. (2025). Iron homeostasis and health: understanding its role beyond blood health – a narrative review. Annals of Medicine & Surgery, 87(6), 3362–3371.

2

[2] Duca, L., Di Pierro, E., Scaramellini, N., Granata, F., & Graziadei, G. (2025). The Relationship Between Non-Transferrin-Bound Iron (NTBI), Labile Plasma Iron (LPI), and Iron Toxicity. International Journal of Molecular Sciences, 26(13).

3

[3] Silva, A. M. N., & Rangel, M. (2022). The (Bio)Chemistry of Non-Transferrin-Bound Iron. Molecules, 27(6).

4

[4] Testa, U., Pelosi, E., & Castelli, G. (2025). Outline of Iron Metabolism, with Emphasis on Erythroid Cells. Mediterranean Journal of Hematology and Infectious Diseases, 17(1).

5

[5] Garbowski, M. W., Cabantchik, I., Hershko, C., Hider, R., & Porter, J. B. (2023). The clinical relevance of detectable plasma iron species in iron overload states and subsequent to intravenous iron-carbohydrate administration. American Journal of Hematology, 98(3), 533–540.

6

[6] Qiu, L., Frazer, D. M., Hu, M., Song, R., Liu, X., Qin, X., Ma, J., Zhou, J., Tan, Z., Ren, F., Collins, J. F., & Wang, X. (2025). Mechanism and regulation of iron absorption throughout the life cycle. Journal of Advanced Research, 77, 107–118.

7

[7] Woei-A-Jin, F. J. S. H., Zheng, S. Z., Kiliçsoy, I., Hudig, F., Luelmo, S. A. C., Kroep, J. R., Lamb, H. J., & Osanto, S. (2020). Lifetime Transfusion Burden and Transfusion-Related Iron Overload in Adult Survivors of Solid Malignancies. The Oncologist, 25(2), e341–e350.

8

[8] Pilo, F., Cilloni, D., Della Porta, M. G., Forni, G. L., Piperno, A., Santini, V., & Angelucci, E. (2022). Iron-mediated tissue damage in acquired ineffective erythropoiesis disease: It’s more a matter of burden or more of exposure to toxic iron form? Leukemia Research, 114.

9

[9] Chen, X., Li, J., Kang, R., Klionsky, D. J., & Tang, D. (2021). Ferroptosis: machinery and regulation. Autophagy, 17(9), 2054–2081.

10

[10] Afzal, S., Abdul Manap, A. S., Attiq, A., Albokhadaim, I., Kandeel, M., & Alhojaily, S. M. (2023). From imbalance to impairment: the central role of reactive oxygen species in oxidative stress-induced disorders and therapeutic exploration. Frontiers in Pharmacology, 14.

11

[11] Huang, X., Liu, R., Zhan, C., Wu, H., Fan, J., Li, Z., & Yang, X. (2024). Aristolochic acid induces acute kidney injury through ferroptosis. Frontiers in Pharmacology, 15.

12

[12] Wareing, M., & Smith, C. P. (2021). Iron Is Filtered by the Kidney and Is Reabsorbed by the Proximal Tubule. Frontiers in Physiology, 12.

13

[13] Packer, M. (2024). Iron homeostasis, recycling and vulnerability in the stressed kidney: A neglected dimension of iron-deficient heart failure. European Journal of Heart Failure, 26(7), 1631–1641.

14

[14] Kabbara, F., Charbel, N., El Khoury, S., Klim, J., Ismail, G., Ismail, F., Fawaz, H., Koussa, S., & Taher, A. (2026). Liver iron concentration and renal dysfunction in β-thalassemia: a case series and exploratory clinical observations. Annals of Hematology, 105(9).

15

[15] Yılmaz, İ., Şimşek, A., Yılmaz, H., Cevizli, D., & Leventoğlu, E. (2025). Renal and cardiac involvements in children with transfusion-dependent thalassemia: A cross-sectional analysis. European Journal of Pediatrics, 184(11).

16

[16] Bruzzese, A., Martino, E. A., Mendicino, F., Lucia, E., Olivito, V., Bova, C., Filippelli, G., Capodanno, I., Neri, A., Morabito, F., Gentile, M., & Vigna, E. (2023). Iron chelation therapy. European Journal of Haematology, 110(5), 490–497.

17

[17] Siregar, O. R., Siregar, R. S., & Lubis, B. (2020). Renal Function in Children with β-Thalassemia Major Treated with Iron Chelating Agent. Indonesian Biomedical Journal, 12(3), 214–219.

18

[18] Kashyap, P., Shikha, D., Thakur, M., & Aneja, A. (2022). Functionality of apigenin as a potent antioxidant with emphasis on bioavailability, metabolism, action mechanism and in vitro and in vivo studies: A review. Journal of Food Biochemistry, 46(4).

19

[19] Liu, S., Zheng, X., Luo, Z., Tang, C., Hu, Y., Peng, Q., Mi, P., Chen, H., & Yao, X. (2024). The synthesis and bioactivity of apigenin derivatives. Fitoterapia, 179.

20

[20] Kejík, Z., Kaplánek, R., Masařík, M., Babula, P., Matkowski, A., Filipenský, P., Veselá, K., Gburek, J., Sýkora, D., Martásek, P., & Jakubek, M. (2021). Iron complexes of flavonoids-antioxidant capacity and beyond. International Journal of Molecular Sciences, 22(2), 1–20.

21

[21] Spiegel, M., & Sroka, Z. (2023). Quantum-mechanical characteristics of apigenin: Antiradical, metal chelation and inhibitory properties in physiologically relevant media. Fitoterapia, 164.

22

[22] Allemailem, K. S., Almatroudi, A., Alharbi, H. O. A., AlSuhaymi, N., Alsugoor, M. H., Aldakheel, F. M., Khan, A. A., & Rahmani, A. H. (2024). Apigenin: A Bioflavonoid with a Promising Role in Disease Prevention and Treatment. Biomedicines, 12(6).

23

[23] Wu, Q., Li, W., Zhao, J., Sun, W., Yang, Q., Chen, C., Xia, P., Zhu, J., Zhou, Y., Huang, G., Yong, C., Zheng, M., Zhou, E., & Gao, K. (2021). Apigenin ameliorates doxorubicin-induced renal injury via inhibition of oxidative stress and inflammation. Biomedicine and Pharmacotherapy, 137.

24

[24] Almaghrabi, S. Y. (2023). Apigenin ameliorates hypercholesterolemic-induced kidney injury via modulating renal KIM-1, Fn1, and Nrf2 signaling pathways. European Review for Medical and Pharmacological Sciences, 27, 1155–1169.

25

[25] Sato, V. H., Sato, H., Sangfuang, M., Nontakham, J., Junyaprasert, V. B., Teeranachaideekul, V., & Morakul, B. (2024). Enhancement of in vitro transcellular absorption and in vivo oral bioavailability of apigenin by self-nanoemulsifying drug delivery systems. Scientific Reports, 14(1).

26

[26] Liu, Q., Mao, T., Liu, F., Chen, B., Liu, Z., Pathak, J. L., & Li, J. (2024). Apigenin alleviates Sjögren’s syndrome-induced salivary gland epithelial cell ferroptosis via ERα signaling-mediated regulation of the ATF3/SLC7A1l axis. International Immunopharmacology, 143.

27

[27] Liang, M., Chen, L., He, Q., Mi, X., Qu, L., Xie, J., & Song, N. (2023). Intraperitoneal injection of iron dextran induces peripheral iron overload and mild neurodegeneration in the nigrostriatal system in C57BL/6 mice. Life Sciences, 320.

28

[28] Larasinta Heriatmo, N., Estuningtyas, A., Soetikno, V., & Poerwaningsih, E. H. (2024). Attenuation of TNF-α and Iron Levels in Renal Hemosiderosis by Phaleria macrocarpa (Scheff.) Boerl Extract in a Rat Iron Overload Model. RESEARCH ARTICLE Indonesian Journal of Pharmacy Indonesian J Pharm, 35(3), 481–490.

29

[29] van Swelm, R. P. L., Wetzels, J. F. M., & Swinkels, D. W. (2020). The multifaceted role of iron in renal health and disease. Nature Reviews Nephrology, 16(2), 77–98.

30

[30] Fisher, A. L., & Babitt, J. L. (2021). Pumping iron in the kidney. Kidney International, 100(3), 505–508.

31

[31] Chultemsuren, M., Song, S.-J., Han, K.-H., & Shin, J.-A. (2025). Iron Overload Accelerates Aging-Associated Kidney Injury in Mice: Implications for Iron Supplementation in the Elderly. Nutrients, 17(16), 2580.

32

[32] Punchai, S., Chaiyagot, N., Artkaew, N., Jusakul, A., Cha’on, U., Thanan, R., Vaeteewoottacharn, K., & Lert-Itthiporn, W. (2024). Iron-induced kidney cell damage: insights into molecular mechanisms and potential diagnostic significance of urinary FTL. Frontiers in Molecular Biosciences, 11.

33

[33] Song, Y., Yang, N., Si, H., Liu, T., Wang, H., Geng, H., Qin, Q., & Guo, Z. (2022). Iron overload impairs renal function and is associated with vascular calcification in rat aorta. BioMetals, 35(6), 1325–1339.

34

[34] Kontoghiorghes, G. J. (2023). The Vital Role Played by Deferiprone in the Transition of Thalassaemia from a Fatal to a Chronic Disease and Challenges in Its Repurposing for Use in Non-Iron-Loaded Diseases. Pharmaceuticals, 16(7).

35

[35] Entezari, S., Haghi, S. M., Norouzkhani, N., Sahebnazar, B., Vosoughian, F., Akbarzadeh, D., Islampanah, M., Naghsh, N., Abbasalizadeh, M., & Deravi, N. (2022). Iron Chelators in Treatment of Iron Overload. Journal of Toxicology, 2022.

36

[36] Sharawy, N., Aboulhoda, B. E., Khalifa, M. M., Morcos, G. N., Morsy, S. A. A. G., Alghamdi, M. A., Khalifa, I. M., & Algaleel, W. A. A. (2024). Amelioration of nephrotoxicity by targeting ferroptosis: role of NCOA4, IREB2, and SLC7a11 signaling. Brazilian Journal of Medical and Biological Research, 57.

37

[37] Kurpios-Piec, D., Majewska-Wierzbicka, M., Czeczot, H., & Podsiad, M. (2021). Flavonoids as Hydroxyl Radical Scavengers, Iron Reductants and Chelators: In Vitro Antioxidant Action. Acta Poloniae Pharmaceutica - Drug Research, 78(5), 635–648.

38

[38] Chen, P., Chen, F., Guo, Z. L., Lei, J., & Zhou, B. (2023). Recent advancement in bioeffect, metabolism, stability, and delivery systems of apigenin, a natural flavonoid compound: challenges and perspectives. Frontiers in Nutrition, 10.

39

[39] Sönmez Aydın, F., Hukkamlı, B., & Budak, H. (2021). Coaction of hepatic thioredoxin and glutathione systems in iron overload-induced oxidative stress. Journal of Biochemical and Molecular Toxicology, 35(4).

40

[40] Li, X., Meng, F., Wang, H., Sun, L., Chang, S., Li, G., & Chen, F. (2023). Iron accumulation and lipid peroxidation: implication of ferroptosis in hepatocellular carcinoma. Frontiers in Endocrinology, 14.

41

[41] Kuang, F., Liu, J., Tang, D., & Kang, R. (2020). Oxidative Damage and Antioxidant Defense in Ferroptosis. Frontiers in Cell and Developmental Biology, 8.

42

[42] Rahma, Estuningtyas, A., Kusmardi, & Poerwaningsih, E. H. (2024). Effect of the combination of deferiprone with ethanolic extract of Phaleria macrocarpa L. fruit in overcoming iron excess in the liver of hemosiderosis model rats. Pharmacia, 71, 1–14.

43

[43] Srichairatanakool, S., Paradee, N., Pokharel, B., Zhong, Y., Kerdto, O., Kiratipaisarl, W., Tantiworawit, A., Chai-Adisaksopha, C., & Srichairatanakool, S. (2026). Iron Overload-Associated Oxidative Stress and Immune Cell Dysfunction in Thalassemia: Integrative Analysis of Hematological, Biochemical, and Flow Cytometric Biomarkers. Antioxidants, 15(4).

44

[44] Piloni, N. E., Vargas, R., Fernández, V., Videla, L. A., & Puntarulo, S. (2021). Effects of acute iron overload on Nrf2-related glutathione metabolism in rat brain. BioMetals, 34(5), 1017–1027.

45

[45] Odeh, D., Oršolić, N., Adrović, E., Gaćina, L., Perić, P., Odeh, S., Balta, V., Lesar, N., & Kukolj, M. (2022). Effects of Volatile Anaesthetics and Iron Dextran on Chronic Inflammation and Antioxidant Defense System in Rats. Antioxidants, 11(4).

46

[46] Dar, N. J., Soriano-Castell, D., & Maher, P. (2026). Sustained dysregulation of iron and glutathione homeostasis induces chronoferroptosis, a persistent ferroptotic adaptation in neuronal cells. Cell Death Discovery, 12(1).

47

[47] Balas, M., Iconaru, S. L., Dinischiotu, A., Buton, N., & Predoi, D. (2023). Response of the Endogenous Antioxidant Defense System Induced in RAW 264.7 Macrophages upon Exposure to Dextran-Coated Iron Oxide Nanoparticles. Pharmaceutics, 15(2).

48

[48] Morales, N. P., Rodrat, S., Piromkraipak, P., Yamanont, P., Paiboonsukwong, K., & Fucharoen, S. (2022). Iron chelation therapy with deferiprone improves oxidative status and red blood cell quality and reduces redox-active iron in β-thalassemia/hemoglobin E patients. Biomedicine and Pharmacotherapy, 145.

49

[49] Merkel, D., Soffer, S., Filanovsky, K., Braester, A., Fibach, E., Dana, M., Ofran, Y., Greenbaum, U., Nagler, A., Amitai, I., & Mittelman, M. (2024). The Effect of Oral Iron Chelator Deferiprone on Iron Overload and Oxidative Stress in Patients with Myelodysplastic Syndromes: A Study by the Israeli MDS Working Group. Acta Haematologica, 147(4), 427–434.

50

[50] Li, J., Koonyosying, P., Korsieporn, W., Paradee, N., Hutachok, N., Xu, H., Ma, Y., Chuljerm, H., & Srichairatanakool, S. (2024). Deferiprone–resveratrol hybrid attenuates iron accumulation, oxidative stress, and antioxidant defenses in iron-loaded human Huh7 hepatic cells. Frontiers in Molecular Biosciences, 11.

51

[51] Han, D., Yao, Y., Chen, L., Miao, Z., & Xu, S. (2022). Apigenin ameliorates di(2-ethylhexyl) phthalate-induced ferroptosis: The activation of glutathione peroxidase 4 and suppression of iron intake. Food and Chemical Toxicology, 164.

52

[52] Wang, X., Li, W., Yuan, W., Wei, Z., Yang, Z., Zhang, Z., Sun, Z., Ji, G., & Hu, H. (2026). Quercetin Attenuates Iron Overload-Induced Renal Injury via Activating Nrf2/xCT/GPX4 Signaling to Inhibit Ferroptosis. Life, 16(3).

53

[53] Shi, X., Zhang, Q., Chang, M., Zhang, Y., Zhao, M. M., Yang, B., Li, P., & Zhang, Y. (2023). Ferroptosis is involved in passive Heymann nephritis in rats. Heliyon, 9(10).

54

[54] Hrelia, S., & Angeloni, C. (2021). New mechanisms of action of natural antioxidants in health and disease II. Antioxidants, 10(8).

55

[55] DeRango-Adem, E. F., & Blay, J. (2021). Does Oral Apigenin Have Real Potential for a Therapeutic Effect in the Context of Human Gastrointestinal and Other Cancers? Frontiers in Pharmacology, 12.

56

[56] Hsu, S. J., Chung, H. C., Chang, C. H., Liao, Y. C., Liu, T. W., Lin, S. M., & Lee, C. K. (2025). Rapid evaluation of apigenin bioavailability and hypouricemic bioactivity by targeted metabolomics study in enterohepatic microenvironment mimetic cell culture model. Food Research International, 209.

57

[57] Berga, M., Logviss, K., Lauberte, L., Paulausks, A., & Mohylyuk, V. (2023). Flavonoids in the Spotlight: Bridging the Gap between Physicochemical Properties and Formulation Strategies. Pharmaceuticals, 16(10).