Antioxidants (Jul 2024)

Apomorphine Suppresses the Progression of Steatohepatitis by Inhibiting Ferroptosis

  • Hiroshi Maeda,
  • Kouichi Miura,
  • Kenichi Aizawa,
  • Oyunjargal Bat-Erdene,
  • Miho Sashikawa-Kimura,
  • Eri Noguchi,
  • Masako Watanabe,
  • Naoya Yamada,
  • Hitoshi Osaka,
  • Naoki Morimoto,
  • Hironori Yamamoto

DOI
https://doi.org/10.3390/antiox13070805
Journal volume & issue
Vol. 13, no. 7
p. 805

Abstract

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The role of ferroptosis in steatohepatitis development is largely unknown. We investigated (1) whether hepatocyte ferroptosis occurs in a gene-modified steatohepatitis model without modifying dietary components, (2) whether ferroptosis occurs at an early stage of steatohepatitis, and (3) whether apomorphine, recently reported as a ferroptosis inhibitor, can ameliorate steatohepatitis. Hepatocyte-specific PTEN KO mice were used. Huh 7 and primary cultured hepatocytes isolated from the mice were used in this study. The number of dead cells increased in 10-week-old PTEN KO mice. This cell death was suppressed by the administration of ferroptosis inhibitor ferrostatin-1 for 2 weeks. Apomorphine also ameliorated the severity of steatohepatitis. Treatment with ferroptosis inhibitors, including apomorphine, decreases the level of lipid peroxidase. Apomorphine suppressed cell death induced by RSL-3 (a ferroptosis inducer), which was not suppressed by apoptosis or necroptosis inhibitors. Apomorphine showed a radical trapping capacity with much more potent activity than ferrostatin-1 and Trolox, a soluble form of vitamin E. In addition, apomorphine activated nrf2 and its downstream genes, including HO-1 and xCT. In conclusion, ferroptosis occurs in steatohepatitis from an early stage in PTEN KO mice. In addition, apomorphine ameliorates the severity of steatohepatitis by inhibiting ferroptosis.

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