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Hepatokine ORM2 suppresses pathological ferritinophagy to prevent acute tissue injury

Hongyi Tang1, Shu Wang1, Fang Liu1

  • 1Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Cell Death & Disease
|April 30, 2026
PubMed

Insights

Orosomucoid 2 (ORM2) protects against acute liver injury by blocking ferritinophagy and iron overload. This hepatokine shows therapeutic potential for various acute tissue injuries.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pathology

Background:

  • Acute tissue injuries cause cellular damage.
  • Cell-intrinsic protective programs mitigate injury.
  • The role of specific hepatokines in injury response is under investigation.

Purpose of the Study:

  • To investigate the role of Orosomucoid 2 (ORM2) in acute liver injury.
  • To elucidate the mechanism by which ORM2 exerts its protective effects.
  • To evaluate ORM2 as a potential therapeutic agent for acute tissue injuries.

Main Methods:

  • Drug-induced acute liver injury model in mice.
  • Orm2 knockout and overexpression studies.
  • Investigation of the FTH-NCOA4-TAX1BP1 interaction.
  • Ischemia-reperfusion injury models in multiple organs.
  • Exogenous ORM2 administration.

Main Results:

  • ORM2 is upregulated during drug-induced acute liver injury.
  • Orm2 knockout exacerbates liver damage; ORM2 overexpression is protective.
  • ORM2 inhibits ferritinophagy by disrupting the FTH-NCOA4-TAX1BP1 complex, preventing iron overload.
  • ORM2 is upregulated in other organs following ischemia-reperfusion injury, indicating liver-organ crosstalk.
  • Exogenous ORM2 ameliorates tissue damage and ferroptosis in various injury models.

Conclusions:

  • ORM2 is an endogenous hepatoprotective factor against acute liver injury.
  • ORM2 suppresses pathological ferritinophagy and iron overload-induced cytotoxicity.
  • ORM2 represents a promising therapeutic candidate for acute tissue injuries involving ferritinophagy.

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