S-Carboxymethylcysteine Mitigates Cyclophosphamide-Induced Hepatotoxicity by Modulating TLR-4/NF-κB Signaling and Redox Homeostasis

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Background Cyclophosphamide (CP) is a widely used chemotherapeutic and immunosuppressive agent. The clinical application of CP is limited by significant hepatotoxicity and other side effects. S-carboxymethylcysteine (SCMC), a mucolytic agent, has gained attention for its potential antioxidant and anti-inflammatory properties. This study evaluated the hepatoprotective efficacy of SCMC against CP-induced liver injury, with a focus on oxidative stress, TLR-4/NF-κB signaling, and the involvement of the key regulatory proteins, cytoglobin, thioredoxin reductase 1 (TXNRD1), and high-mobility group box 1 (HMGB1). Methods Rats were pretreated with SCMC for seven days, followed by a single dose of CP on the fifth day. Blood and liver were collected for biochemical and histopathological examinations. Results CP administration resulted in a marked increase in serum transaminases alongside a reduction in albumin levels, accompanied by significant histopathological damage in the liver. SCMC effectively alleviated liver function biomarkers and ameliorated CP-induced histopathological changes. Oxidative stress induced by CP was evident through elevated malondialdehyde and diminished glutathione and antioxidant enzyme activities, all of which were counteracted by SCMC. Furthermore, CP upregulated TLR-4, NF-κB p65, pro-inflammatory cytokines, Bax, and caspase-3, while downregulating the expression of Bcl-2, cytoglobin, TXNRD1, and HMGB1. SCMC suppressed TLR-4/NF-κB signaling, pro-inflammatory cytokine release, Bax, and caspase-3, while restoring the expression of Bcl-2, cytoglobin, TXNRD1, and HMGB1. Conclusion SCMC confers protection against CP-induced hepatotoxicity by alleviating oxidative stress, inhibiting TLR-4/NF-κB-mediated inflammation, attenuating apoptosis, and upregulating cytoglobin, TXNRD1, and HMGB1. These findings demonstrate the therapeutic potential of SCMC in mitigating hepatotoxicity associated with CP treatment.

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