Modulation of oxidative stress, inflammation, and apoptosis and restoration of Sirt1/Nrf2/HO-1 signaling by myricetin protect against cyclophosphamide-induced hepatotoxicity in rats.

Cyclophosphamide (CP), a widely used immunosuppressive and chemotherapeutic agent, is associated with several adverse effects, including hepatotoxicity. Myricetin (MyR), a natural flavonoid, possesses significant antioxidant and anti-inflammatory properties. This study employed a rat model to investigate the hepatoprotective effects of MyR against CP-induced liver injury. Rats were concurrently treated with MyR (25 and 50 mg/kg, orally) and CP (30 mg/kg, intraperitoneally) for 10 days. CP administration significantly elevated liver injury biomarkers, including alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and bilirubin levels. Histopathological alterations were also observed in hepatic tissues following CP administration. In addition, hepatic tissues from CP-treated rats exhibited elevated nitric oxide and malondialdehyde (MDA) levels, indicating enhanced oxidative stress. Simultaneously, antioxidant defenses, including catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD), were significantly reduced. CP also triggered an inflammatory response characterized by elevated NF-κB p65 and pro-inflammatory cytokine levels (TNF-α, IL-1β, and IL-6) in hepatic tissues. Moreover, apoptotic markers, including caspase-3 and Bax, were significantly increased, whereas Bcl-2 levels were reduced. Notably, MyR treatment significantly attenuated hepatic histopathological alterations, oxidative stress, inflammation, and apoptosis in CP-administered rats. The protective effects of MyR were associated with restoration of Sirt1/Nrf2/HO-1 signaling in hepatic tissues. These findings suggest that MyR may represent a potential protective candidate against CP-induced hepatotoxicity.