Modulation of NF-κB/NLRP3 inflammasome axis Nrf2/HO-1 signaling and attenuation of oxidative stress mediate the protective effect of ambroxol against cyclophosphamide cardiotoxicity

Abstract

Despite its potent chemotherapeutic efficacy, cyclophosphamide (CP) is associated with severe cardiac complications, limiting its clinical utility. Recent evidence suggests that the mucolytic agent ambroxol (ABX) exhibits antioxidant and anti-inflammatory properties, making it a candidate for mitigating CP cardiotoxicity. This study explored the protective effects of ABX against CP-mediated cardiotoxicity, with emphasis on oxidative stress, NF-κB/NLRP3 inflamamsome axis and Nrf2/HO-1 signaling. Rats were administered ABX (20 mg/kg) for 7 days and received a single injection of CP (100 mg/kg) on day 5, and blood and heart samples were collected for analyses. CP administration induced significant cardiac dysfunction, marked by elevated LDH, CK-MB, and troponin-I, alongside histopathological evidence of myocardial injury. ABX alleviated cardiac biomarkers, prevented histopathological alterations, reduced lipid peroxidation, and restored antioxidant defenses. CP upregulated NF-κB p65, NLRP3, ASC1, caspase-1, gasdermin D, and IL-1β, and suppressed Nrf2 and HO-1 in the heart of rats. ABX suppressed the NF-κB/NLRP3 inflamamsome axis mediators and upregulated Nrf2 and HO-1. In silico data revealed the binding affinity of ABX towards NF-κB p65 and NLRP3 and ASC1 PYD domains. In conclusion, ABX confers significant protection against CP-induced cardiotoxicity through multifaceted mechanisms, including attenuation of oxidative stress, inhibition of NF-κB/NLRP3 inflamamsome axis, and upregulation of Nrf2/HO-1 signaling. These findings suggest that ABX could serve as an effective adjunct therapy to improve the safety profile of CP in clinical oncology.