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

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.