Mechanistic insights into the hepatoprotective role of rabeprazole against cyclophosphamide-induced hepatotoxicity via AMPK/SIRT1 activation and suppression of TLR4/NF-κB and MAPK pathways.

aimsThis study evaluates the ability of Rabeprazole (RAB) in counteracting cyclophosphamide (CP)-induced hepatotoxicity, focusing on its regulatory impact on key molecular signaling pathways, particularly AMPK/SIRT1, PI3K/Akt, TLR4/NF-κB, and MAPK, as well as its influence on NLRP3 inflammasome activation. MAIN

methodsRats were assigned into four distinct groups (n = 8 each): a control group administered distilled water; a CP group administered a single intraperitoneal dose of CP (200 mg/kg) on the seventh day; and two treatment groups pretreated orally with RAB (10 or 30 mg/kg/day) for ten days, with CP delivered on day 7. Biochemical, histological, immuno-histochemical, qRT-PCR, and western blotting procedures were conducted to evaluate liver function, oxidative status, and molecular signaling. KEY

findingsRats exposed to CP showed marked increases in hepatic markers (ALT, AST), together with decreases in antioxidative markers (GSH, Nrf2, HO-1) and increases in MDA, MPO, iNOS, as well as pro-inflammatory markers represented by IL-6, TNF-α, IL-1β. Hepatic expression of AMPK, SIRT1, and PI3K/Akt was markedly suppressed, while TLR4, NF-κB p65, MAPK proteins, and NLRP3 were upregulated. RAB pretreatment dose-dependently restored hepatic enzyme levels, corrected redox imbalance, reduced cytokine release, and normalized gene and protein expression profiles. Histopathological improvements further corroborated the protective effect of RAB. SIGNIFICANCE: These results indicate that Rabeprazole may serve as an effective therapeutic option to reduce CP-induced liver injury through its multifaceted protective actions, highlighting the necessity for more extensive research in subsequent studies.