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<p>Arsenic trioxide (As<sub>2</sub>O<sub>3</sub>) is an effective therapeutic agent for acute promyelocytic leukemia. However, its clinical application is limited by hepatotoxicity, mainly linked to oxidative stress, inflammatory activation, and mitochondrial dysfunction. This study investigated whether ellagic acid (EA) and montelukast (MK), alone or together, protect against As<sub>2</sub>O<sub>3</sub>-induced liver injury in mice. Male NMRI mice were treated with As<sub>2</sub>O<sub>3</sub> in the presence or absence of EA and MK for 10&#xa0;days. After treatment, we performed biochemical, molecular, mitochondrial, and histopathological evaluations. As<sub>2</sub>O<sub>3</sub> exposure led to pronounced hepatic injury, which was evident from elevated liver enzyme levels, increased lipid peroxidation, raised pro-inflammatory cytokines, reduced mitochondrial membrane potential, and increased apoptosis indices. Administration of EA or MK alone partly reduced several of these parameters. In contrast, concurrent use of EA and MK produced more marked improvements, including normalization of liver enzymes, enhanced antioxidant enzyme activity, lower pro-inflammatory and apoptotic markers, and preserved mitochondrial function. These protective effects were supported by consistently improved liver histopathology. In conclusion, combined EA and MK administration reduces As<sub>2</sub>O<sub>3</sub>-induced hepatotoxicity. This protection occurs by modulating oxidative stress, inflammation, and mitochondrial-dependent apoptosis. These findings indicate that targeting several processes could help reduce liver side effects from arsenic-based chemotherapy.</p>

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Ellagic acid and montelukast mitigate arsenic trioxide–induced hepatotoxicity via modulation of oxidative stress, inflammatory pathways, and mitochondrial apoptosis

  • 期刊论文

  • 发表日期：

    2026年6月15日

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  • Maryam Gharibi,
  • Ali Akbar Oroojan,
  • Mohammad Amin Behmanesh,
  • Neda Amirgholami,
  • Hooman Etedali,
  • Soheila Alboghobeish

摘要

Arsenic trioxide (As2O3) is an effective therapeutic agent for acute promyelocytic leukemia. However, its clinical application is limited by hepatotoxicity, mainly linked to oxidative stress, inflammatory activation, and mitochondrial dysfunction. This study investigated whether ellagic acid (EA) and montelukast (MK), alone or together, protect against As2O3-induced liver injury in mice. Male NMRI mice were treated with As2O3 in the presence or absence of EA and MK for 10 days. After treatment, we performed biochemical, molecular, mitochondrial, and histopathological evaluations. As2O3 exposure led to pronounced hepatic injury, which was evident from elevated liver enzyme levels, increased lipid peroxidation, raised pro-inflammatory cytokines, reduced mitochondrial membrane potential, and increased apoptosis indices. Administration of EA or MK alone partly reduced several of these parameters. In contrast, concurrent use of EA and MK produced more marked improvements, including normalization of liver enzymes, enhanced antioxidant enzyme activity, lower pro-inflammatory and apoptotic markers, and preserved mitochondrial function. These protective effects were supported by consistently improved liver histopathology. In conclusion, combined EA and MK administration reduces As2O3-induced hepatotoxicity. This protection occurs by modulating oxidative stress, inflammation, and mitochondrial-dependent apoptosis. These findings indicate that targeting several processes could help reduce liver side effects from arsenic-based chemotherapy.