The protective effect of ambroxol against cyclophosphamide-induced acute kidney injury involves Nrf2/HO-1 signaling upregulation and suppression of oxidative and inflammatory damage.

Cyclophosphamide (CP) is a widely used chemotherapeutic agent whose clinical efficacy is often limited by its side effects, including nephrotoxicity. Oxidative stress and inflammation are central to CP-induced acute kidney injury (AKI). Ambroxol (ABX), a clinically approved mucolytic agent, has demonstrated antioxidant and anti-inflammatory properties that may be repurposed for nephroprotection. This study investigated the protective effects of ABX against CP-induced nephrotoxicity in rats and explored the underlying molecular mechanisms. Adult male rats received ABX (20 mg/kg/day) orally for seven consecutive days, with CP (100 mg/kg, i.p.) given on the fifth day. CP administration resulted in significant renal dysfunction, as indicated by elevated serum creatinine, BUN, uric acid, and Kim-1 levels. Histopathological analysis revealed glomerular degeneration, tubular damage, collagen deposition, and iron accumulation. CP also induced oxidative stress, evidenced by increased MDA and decreased GSH, SOD, and catalase, along with upregulation of NF-κB, elevated TNF-α and IL-1β levels, and increased cleaved caspase-3 expression. ABX reduced MDA, enhanced antioxidant defenses, and suppressed NF-κB and pro-inflammatory cytokines. ABX attenuated apoptosis as evidenced by reduced caspase-3 expression and concurrently modulated redox-sensitive signaling by upregulating Nrf2 and HO-1 expression and activity while downregulating Keap-1. ABX showed in silico binding affinity toward NF-κB, Keap-1, and HO-1. In conclusion, these findings suggest that ABX confers nephroprotection against CP-induced injury primarily through its antioxidant, anti-inflammatory, and anti-apoptotic actions, partly via modulation of the Keap-1/Nrf2/HO-1 pathway. These findings support potential repurposing of ABX as a nephroprotective adjuvant during CP chemotherapy and warrant further clinical investigation.