Secukinumab’ Cardioprotective Effect in Doxorubicin-induced cardiomyopathy: Targeting the NF-κB/NLRP3 Pathway in Rats

Abstract

<title>Abstract</title> Doxorubicin (DOX) is a medication employed in the treatment of cancer as a chemotherapeutic agent. However, it induces cardiotoxicity via activating inflammatory pathways. Cytokines dysregulation is a key factor that can lead to activation of inflammatory mechanisms. Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that triggers pathogenic immune responses. The objective of this study was to investigate the defensive power of secukinumab (SEC), a fully human monoclonal IgG1/κ antibody targeting IL-17A, designed to combat DOX-induced cardiotoxicity (DIC). Male Wistar rats were treated with DOX and co-treated with SEC for two weeks. The results showed that DOX caused heart tissue injury, increased cardiotoxicity markers significantly (P &lt; 0.0001), oxidative stress and inflammation. Additionally, DOX activated the nuclear factor kappa beta (NF-κB) pathway and Pyrin domain containing 3 (NLRP3) inflammasome, potentially contributing to DIC. The co-treatment with SEC successfully reversed all DOX-related abnormalities by restoring cardiac functions to normal levels, decreasing levels of inflammatory cytokines, including IL-17A and Interleukin-1β (IL-1β), and improving oxidative stress by lowering malondialdhyde (MDA) levels and increasing reduced glutathione (GSH) levels. Furthermore, it also decreased the upregulation of the NF-κB/NLRP3 axis induced by doxorubicin. This study highlights the protective properties of SEC against DIC by modulating the NF-κB/NLRP3/caspase1/IL-1β axis.