Ellagic Acid and Montelukast Mitigate Arsenic Trioxide-Induced Hepatotoxicity via Modulation of Oxidative Stress, Inflammatory Pathways, and Mitochondrial Apoptosis

Although arsenic trioxide (As₂O₃) is an effective agent in treating acute promyelocytic leukemia, its use is limited by severe hepatotoxicity primarily mediated through oxidative stress, inflammatory responses, and apoptosis. Ellagic acid (EA) and montelukast (MK) possess protective properties against these damaging processes. This study aimed to investigate the protective effects of EA and MK, individually and in combination, against As₂O₃-induced hepatotoxicity in an experimental mouse model. Forty-two male NMRI mice were divided into seven groups and treated with As₂O₃, EA, MK, or their combinations for 10 days. Following treatment, liver and blood samples were collected, and liver biochemical indices, oxidative stress markers, mitochondrial function, reactive oxygen species (ROS), myeloperoxidase (MPO) levels, expression of inflammatory proteins (TLR4, VCAM-1, MPO), cytokines (TNF-α, IL-1β, IL-6), apoptosis indices (caspase-3, cytochrome c, DNA fragmentation index), and gene expression of Bax, Bcl-2, and Survivin were evaluated. As₂O₃ administration significantly increased liver injury indices, lipid peroxidation, mitochondrial dysfunction, inflammation, and activated apoptotic pathways. Treatment with EA or MK alone showed relative protective effects. Notably, the combination of EA and MK resulted in significant reductions in ALT, AST, MDA, ROS, TNF-α, IL-1β, IL-6, TLR4, VCAM-1, and apoptotic markers. Histopathological examination also revealed improved liver tissue structure in the combination group. The combination of EA and MK exerted potent and multifaceted protective effects against As₂O₃-induced hepatotoxicity by simultaneously targeting oxidative stress, inflammation, and apoptosis. These findings suggest the synergistic efficacy of EA and MK and support their potential as adjuvants to improve tolerability and reduce side effects of As₂O₃ therapy.