Metformin ameliorates doxorubicin-induced cardiotoxicity targeting HMGB1/TLR4/NLRP3 signaling pathway in mice

Aims: Oxidative stress and inflammation have been linked to doxorubicin (DOX)-induced cardiotoxicity, while the exact molecular processes are currently under investigation. The goal of this study is to investigate Met-formin's preventive role in cardiotoxicity induced by DOX.Materials and methods: Male albino mice were divided randomly into 4 groups. Metformin (Met) 200 mg/kg orally (p.o.) was given either alone or when combined with a single DOX (15 mg/kg; i.p.). A control group of 5 mice was also provided. Met was initiated 7 days before DOX, lasting for 14 days. Besides, docking studies of Met towards HMGB1, NF-kB, and caspase 3 were performed.Key findings: Heart weight, cardiac troponin T (cTnT), creatine kinase Myocardial Band (CK-MB) levels, malondialdehyde (MDA), and nitric oxide (NO) contents all increased significantly when comparing the DOX group to the control normal group. Conversely, there was a substantial decline in superoxide dismutase (SOD) and glutathione peroxidase (GSH). DOX group depicts a high expression of TLR4, HMGB1, and caspase 3. Immunohistochemical staining revealed an increase in NLRP3 inflammasome and NF-Kappa B expressions alongside histopathological modifications. Additionally, Met dramatically decreased cardiac weight, CK-MB, and cTnT while maintaining the tissues' histological integrity. Inflammatory biomarkers, including HMGB1, TLR4, NF-Kappa B, inflammasome, and caspase 3 were reduced after Met therapy. Furthermore, molecular docking studies sug-gested the antagonistic activity of Met towards HMGB1, NF-Kappa B, and caspase 3 target receptors.Significance: According to recent evidence, Met is a desirable strategy for improving cardiac toxicity produced by DOX by inhibiting the HMGB1/NF-Kappa B inflammatory pathway, thus preserving heart function.

Automated summary

The study aims to investigate the preventive role of Metformin in DOX-induced cardiotoxicity. The results showed that Metformin reduced cardiac toxicity caused by DOX, possibly by inhibiting the HMGB1/NF-Kappa B inflammatory pathway and preserving heart function.