Attenuation of NF-κB/NLRP3 inflammasome axis and oxidative stress, and upregulation of Nrf2/HO-1 signaling mediate the protective effect of S-carboxymethylcysteine against cyclophosphamide-induced cardiotoxicity

Cyclophosphamide (CP) is a potent chemotherapeutic and immunosuppressant agent used in the management of lymphoproliferative disorders and solid tumors. However, it induces cardiotoxicity and other severe adverse effects, thereby limiting its clinical application, highlighting the need for safe and effective cardioprotective agents. This study investigates the cardioprotective potential of carbocysteine (S-carboxymethylcysteine (SCMC)), a mucolytic agent with emerging pleiotropic properties, against CP-induced toxicity. The study explores the effect of SCMC on oxidative stress, NF-κB/NLRP3 inflammasome axis and Nrf2/HO-1 signaling. Rats received SCMC for 7 days and a single CP dose on day 5. CP provoked severe cardiac injury, evidenced by increased CK-MB, LDH, and troponin-I, alongside histopathological alterations, including vascular congestion, cytoplasmic vacuolation, hypertrophy, and nuclear pyknosis. SCMC significantly alleviated cardiac biomarkers and mitigated tissue damage in CP-treated rats. CP increased MDA, decreased antioxidants, increased cardiac NF-κB, IL-1β, and gasdermin D, upregulated NLRP3, ASC1, and caspase-1, and diminished Nrf2 and HO-1. SCMC reduced MDA, enhanced antioxidant defenses, and downregulated NF-κB, NLRP3, ASC, caspase-1, gasdermin D, and IL-1β in CP-administered rats. In addition, SCMC enhanced the expression of Nrf2 and activity of HO-1 in the heart of CP-administered rats. In conclusion, these findings demonstrate that SCMC mitigates CP-induced cardiotoxicity by targeting oxidative injury and inflammatory signaling. Its cardioprotective mechanism includes mitigation of oxidative stress and NF-κB/NLRP3 inflammasome axis, and upregulation of Nrf2/HO-1 pathway. Given its established clinical safety, SCMC may represent a translatable adjunctive therapy to protect against CP-induced cardiotoxicity. However, further studies and clinical trials are warranted to confirm these findings.