Comparative Hepatoprotective Effects of Dapagliflozin and Silymarin Against Cyclophosphamide-Induced Liver Injury in Rats: Involvement of Nrf2/HO-1, HNF4α, and HNF6 Pathways

Authors

  • Afrah Thiab Hlail Department of Pharmacology and Toxicology, College of Pharmacy, Thi-Qar University , Thi-Qar, Iraq
  • Nada Naji Al-Shawi Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq

DOI:

https://doi.org/10.31351/vol35iss2pp155-165

Abstract

Background: Cyclophosphamide (Cpd), a common immunosuppressive and chemotherapeutic drug, can cause hepatotoxicity by inducing inflammation and oxidative stress. Dapagliflozin (Dapa) and other sodium-glucose cotransporter-2 inhibitors (SGLT2i) have anti-inflammatory and antioxidant properties, and Silymarin is a natural compound extracted from the seeds of the milk thistle plant (Silybum marianum). It is best known for its antioxidant, anti-inflammatory, and hepatoprotective effects.Objective: By measuring oxidative stress, inflammation, and liver regeneration parameters, with an emphasis on the Nrf2/HO-1 pathway and hepatocyte nuclear factors (HNF4α and HNF6), Dapa's hepatoprotective effects in comparison to Sil on Cpd-induced liver injury will be evaluated. Methods: Five (5) groups of male rats ten rats each were created: control, vehicle (Na-CMC), Cpd (30mg/kg), Cpd + Dapa (3mg/kg), and Cpd + Sil (200mg/kg).. Rat liver tissue was examined for Nrf2, HO-1 (qRT-PCR), HNF4α (ELISA), and HNF6 (Western blot) levels after ten days. Results: Cpd significantly reduced Nrf2, HO-1, HNF4α, and HNF6 levels (*p < 0.0001). Dapa and Sil restored these markers, with Dapa showing superior upregulation of Nrf2 (2.182 ± 0.540 vs. Cpd 0.244 ± 0.096) and HO-1 (2.051 ± 0.533 vs. CP 0.487 ± 0.178) (*p< 0.0001). Dapa also significantly increased HNF4α (2135 ± 297.9 vs. CP 229.5 ± 50.21) and HNF6 (3.635 ± 0.610 vs. CP 0.515 ± 0.255) (*p< 0.001), outperforming Sil in enhancing HNF6 (*p < 0.05). Conclusion: Dapa ameliorates Cpd-induced hepatotoxicity by activating the Nrf2/HO-1 pathway and restoring HNF4α/HNF6 expression, demonstrating comparable or superior efficacy to Sil. These findings highlight Dapa’s potential as an adjunct therapy to mitigate chemotherapy-induced hepatotoxicity

How to Cite

1.
Afrah Thiab Hlail, Nada Naji Al-Shawi. Comparative Hepatoprotective Effects of Dapagliflozin and Silymarin Against Cyclophosphamide-Induced Liver Injury in Rats: Involvement of Nrf2/HO-1, HNF4α, and HNF6 Pathways. Iraqi Journal of Pharmaceutical Sciences [Internet]. 2026 Jun. 24 [cited 2026 Jun. 25];35(2):155-6. Available from: https://bijps.uobaghdad.edu.iq/index.php/bijps/article/view/4673

Publication Dates

Received

2025-06-03

Revised

2025-06-12

Accepted

2025-11-28

Published Online First

2026-06-24

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