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

作者：Ayema Rehman, Muhammad Abid, Zubaid Rafique, Jehanzeb Khan, Muhammad Waqas, Ihsan Ul Haq, Muhammad Khalid Tipu, Humaira Fatima, Nadeem Irshad · 发表于：Journal of Biochemical and Molecular Toxicology · 年份：2025 · DOI：10.1002/jbt.70433 · 被引用次数：2 · 研究领域：Chemotherapy-induced cardiotoxicity and mitigation、Electron Spin Resonance Studies、Bioactive Compounds and Antitumor Agents

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‐inflamma...