Protective Effect of Santonin Against Doxorubicin Induced Cardiotoxicity via TLR4/NF‐κB, Nrf2/HO‐1, and Caspase‐3 Pathway Modulation in Rats

Ayema Rehman; Muhammad Abid; Zubaria Rafique; Jehan Zeb Khan; Muhammad Waqas; Ihsan Ul Haq; Muhammad Khalid Tipu; Humaira Fatima; Nadeem Irshad

doi:10.1002/jbt.70433

journal article Aug 01, 2025

Protective Effect of Santonin Against Doxorubicin Induced Cardiotoxicity via TLR4/NF‐κB, Nrf2/HO‐1, and Caspase‐3 Pathway Modulation in Rats

Ayema Rehman Muhammad Abid

Zubaria Rafique Jehan Zeb Khan Muhammad Waqas

Ihsan Ul Haq

Muhammad Khalid Tipu Humaira Fatima Nadeem Irshad

Journal of Biochemical and Molecular Toxicology Vol. 39 No. 8 · Wiley

View at Publisher Save 10.1002/jbt.70433

Abstract

ABSTRACT

Doxorubicin (DOX) is a potential chemotherapeutic drug, but its practical use is limited as it causes dose‐dependent cardiotoxicity. This study aims to explore the cardioprotective role and mechanism of Santonin (Sant) against doxorubicin‐induced cardiotoxicity. Initially, Sant's pharmacokinetics, toxicity, and molecular docking with target proteins were determined computationally. In an in vivo study, Sant pretreatment (30 mg/kg and 60 mg/kg) was administered daily via per oral (PO) route, and cardiotoxicity was induced in rats by a single intraperitoneal (IP) injection of DOX (15 mg/kg). The results revealed that Sant demonstrates favorable pharmacokinetics and low toxicity; therefore, it can be administered orally. Moreover, molecular docking studies revealed a significant interaction of Sant with target proteins. Sant pretreatment significantly recovered DOX‐induced neurobehavioral changes, body weight changes, relative heart weight, serum cardiac biomarker levels (LDH, CK‐MB, Trop I), serum electrolyte levels (Na
+
, K
+
, Cl
−
), and oxidative stress by modulation of antioxidant and oxidative stress markers levels. Sant improved histopathological alterations and cardiac fibrosis. In addition, Sant downregulates inflammatory mediators such as TLR4 and NF‐κB, upregulates oxidative stress sensors such as Nrf2 and HO‐1, downregulates caspase‐3 apoptotic marker, and reverses the DOX‐induced DNA damage in cardiac tissue. Sant also decreases the levels of pro‐inflammatory cytokines such as TNF‐α and IL‐1β in DOX‐treated rats. This study suggests for the first time that Sant can prove to be the potential therapeutic option for mitigating DOX‐induced cardiotoxicity via modulation of inflammatory (TLR4/NF‐κB), oxidative stress (Nrf2/HO‐1), and apoptotic (Caspase‐3) signaling pathways.

Topics

No keywords indexed for this article. Browse by subject →

References

73

[1]

10.1007/s11912-022-01309-w

[2]

10.3332/ecancer.2022.1430

[3]

10.1016/j.mam.2023.101205

[4]

10.1007/s00210-023-02382-z

[5]

Doxorubicin-mediated cardiac dysfunction: Revisiting molecular interactions, pharmacological compounds and (nano)theranostic platforms

Xiaofeng Li

Environmental Research 10.1016/j.envres.2023.116504

[6]

10.3390/ph4081088

[7]

Lu H. T. "Beta‐Blocker Use and Risk of Symptomatic Bradyarrhythmias: A Hospital‐Based Case‐Control Study" Journal of Geriatric Cardiology: JGC (2016)

[8]

10.3389/fcvm.2020.00115

[9]

10.3390/ijerph19148373

[10]

10.2217/fon-2018-0210

[11]

10.1002/pbc.25043

[12]

10.3390/ijms221810037

[13]

10.1016/j.ejmech.2019.04.066

[14]

10.1002/anie.200390318

[15]

10.1177/0748233713498454

[16]

Studies on the Antiinflammatory, Antipyretic and Analgesic Activities of Santonin

Mohammed M. Al-Harbi, Shoeb Qureshi, Mohammad M. Ahmed et al.

Japanese Journal of Pharmacology 10.1254/jjp.64.135

[17]

10.1007/s11095-013-1101-9

[18]

10.1080/14786419.2014.996150

[19]

10.1016/0378-8741(88)90007-4

[20]

10.1007/s00044-016-1633-8

[21]

10.1021/acsomega.2c04867

[22]

10.3390/molecules28145413

[23]

10.1002/ddr.430340102

[24]

Aghvami M. "Selective Cytotoxicity of α‐Santonin From the Persian Gulf Sponge Dysidea avara on Pediatric ALL B‐Lymphocytes via Mitochondrial Targeting" Asian Pacific Journal of Cancer Prevention: APJCP (2018)

[25]

10.1016/j.ejmech.2013.01.003

[26]

10.1039/c6md00527f

[27]

10.4314/tjpr.v19i4.13

[28]

Drug-like properties and the causes of poor solubility and poor permeability

Christopher A. Lipinski

Journal of Pharmacological and Toxicological Metho... 10.1016/s1056-8719(00)00107-6

[29]

SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules

Antoine Daina, Olivier Michielin, Vincent Zoete

Scientific Reports 10.1038/srep42717

[30]

10.1002/minf.201000151

[31]

Pharmacophore-Based Screening, Molecular Docking, and Dynamic Simulation of Fungal Metabolites as Inhibitors of Multi-Targets in Neurodegenerative Disorders

Danish Iqbal, Mohammed Alsaweed, Qazi Mohammad Sajid Jamal et al.

Biomolecules 10.3390/biom13111613

[32]

10.1177/20587384211051993

[33]

10.3109/13880209.2012.729065

[34]

10.1590/s0100-879x2008000200010

[35]

10.1016/j.biopha.2018.12.047

[36]

10.1016/j.neubiorev.2021.06.014

[37]

10.1016/j.lfs.2016.06.012

[38]

10.1016/j.jep.2021.114004

[39]

10.3389/fchem.2023.1268949

[40]

Tissue sulfhydryl groups

George L. Ellman

Archives of Biochemistry and Biophysics 10.1016/0003-9861(59)90090-6

[41]

10.3390/biom10060816

[42]

10.1016/j.biopha.2021.111567

[43]

10.3390/jpm13040649

[44]

10.3390/ijms22116084

[45]

10.1016/j.intimp.2022.108604

[46]

10.1007/s10565-008-9072-z

[47]

10.1002/jbt.70084

[48]

10.1007/s10787-023-01225-w

[49]

10.1016/j.yjmcc.2012.03.006

[50]

Computational Methods in Drug Discovery

Gregory Sliwoski, Sandeepkumar Kothiwale, Jens Meiler et al.

Pharmacological Reviews 10.1124/pr.112.007336

Showing 50 of 73 references

Metrics

1

Citations

73

References

Details

Published: Aug 01, 2025
Vol/Issue: 39(8)
License: View

Authors

A

Ayema Rehman