2. Academic Validation
  3. Verbenalin attenuates hepatic damage and mitochondrial dysfunction in alcohol-associated steatohepatitis by regulating MDMX/PPARα-mediated ferroptosis

Verbenalin attenuates hepatic damage and mitochondrial dysfunction in alcohol-associated steatohepatitis by regulating MDMX/PPARα-mediated ferroptosis

  • J Ethnopharmacol. 2023 May 10:307:116227. doi: 10.1016/j.jep.2023.116227.
Jiahui Dong 1,  Changlin Du 1,  Chuanting Xu 1,  Qi Wang 1,  Zhonghao Wang 1,  Qian Zhu 1,  Xiongwen Lv 2,  Lei Zhang 2,  Jun Li 1,  Cheng Huang 1,  Hua Wang 3,  Taotao Ma 4
Affiliations

Affiliations

  • 1 Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
  • 2 Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Center of Traditional Chinese Medicine Formula Granule, Anhui Medical University, China.
  • 3 Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230036, China. Electronic address: wanghua@ahmu.edu.cn.
  • 4 Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Center of Traditional Chinese Medicine Formula Granule, Anhui Medical University, China. Electronic address: mataotao@ahmu.edu.cn.
PMID: 36739928 DOI: 10.1016/j.jep.2023.116227
Abstract

Ethnopharmacological relevance: Verbenalin is a major compound in Verbena officinalis L. Verbena officinalis L was first recorded in the 'Supplementary Records of Famous Physicians.' Verbenalin (VE) is its active constituent and has been found to have many biological effects, including anti-obesity, anti-inflammatory, and antioxidant activities, removing jaundice, and treating malaria. It could treat lump accumulation, dysmenorrhea, throat obstruction, edema, jaundice, and malaria. Palmitic acid (PA), oleic acid (OA), ethanol, and acetaminophen liver injuries have been proven to benefit from verbenalin.

Aim of the study: To study the effects of verbenalin on the prevention of alcoholic steatohepatitis (ASH) through the regulation of oxidative stress and mitochondrial dysfunction by regulating MDMX (Murine double minute X)/PPARα (Peroxisome Proliferator-activated Receptor alpha)-mediated Ferroptosis.

Material and methods: C57BL/6 mice treated with alcohol followed by the Gao-Binge protocol were administered verbenalin by gavage simultaneously. The mitochondrial mass and morphology were visualized using TEM. AML-12 cells were stimulated with ethanol to mimic ASH in vitro. Western blotting, co-immunoprecipitation, and kit determination were simultaneously performed. The target protein of verbenalin was identified by molecular docking, and cellular thermal shift assay (CETSA) further confirmed its interactions.

Results: Verbenalin alleviates oxidative stress and Ferroptosis in alcohol-associated steatohepatitis. To elucidate the molecular mechanism by which verbenalin inhibits abnormal mitochondrial dysfunction, molecular docking was performed, and MDMX was identified as the target protein of verbenalin. CETSA assays revealed a specific interaction between MDMX and verbenalin. Co-immunoprecipitation demonstrated that PPARα played a critical role in promoting the ability of MDMX to affect Ferroptosis. Verbenalin regulates MDMX/PPARα-mediated Ferroptosis in AML-12 cells.

Conclusion: Verbenalin regulates Ferroptosis and highlights the therapeutic potential of verbenalin and Ferroptosis inhibition in reducing alcoholic steatohepatitis.

Keywords

Alcoholic steatohepatitis; Ferroptosis; MDMX; PPARα; Verbenalin.

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