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<p>Acute tissue injuries trigger rapid cellular damage, but cell-intrinsic protective programs attenuate pathology through regulatory axes. Here, we demonstrate that Orosomucoid 2 (ORM2), a hepatokine, is significantly upregulated during drug-induced acute liver injury. Knock out <i>Orm2</i> exacerbates liver damage, while its overexpression provides protection, identifying ORM2 as an endogenous hepatoprotective factor during acute liver injury. Mechanistically, ORM2 disrupts the FTH-NCOA4-TAX1BP1 interaction, thereby blocking ferritinophagy and preventing iron overload-induced cytotoxicity. Furthermore, acute ischemia-reperfusion injuries in other organs also trigger hepatic ORM2 upregulation and secretion, demonstrating liver-organ crosstalk via the circulatory system. Exogenous administration of ORM2 effectively ameliorates ferroptosis and tissue damage in multiple ischemia-reperfusion injury models. Collectively, our results identify the hepatokine ORM2 as a key suppressor of pathological ferritinophagy. This function positions ORM2 protein as a potential therapeutic candidate for acute tissue injuries driven by ferritinophagy-mediated iron overload.</p>

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Hepatokine ORM2 suppresses pathological ferritinophagy to prevent acute tissue injury

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月30日

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  • Hongyi Tang,
  • Shu Wang,
  • Fang Liu,
  • Boqian Shen,
  • Feng Jiang,
  • Xinyuan Xiong,
  • Nan Yang,
  • Huiqin Zhu,
  • Rulin Zhang,
  • Dongge Xia,
  • Cong Cong,
  • Yan Lu,
  • Jie Yang,
  • Jun Wu,
  • Bing Zhou,
  • Xuxu Sun

摘要

Acute tissue injuries trigger rapid cellular damage, but cell-intrinsic protective programs attenuate pathology through regulatory axes. Here, we demonstrate that Orosomucoid 2 (ORM2), a hepatokine, is significantly upregulated during drug-induced acute liver injury. Knock out Orm2 exacerbates liver damage, while its overexpression provides protection, identifying ORM2 as an endogenous hepatoprotective factor during acute liver injury. Mechanistically, ORM2 disrupts the FTH-NCOA4-TAX1BP1 interaction, thereby blocking ferritinophagy and preventing iron overload-induced cytotoxicity. Furthermore, acute ischemia-reperfusion injuries in other organs also trigger hepatic ORM2 upregulation and secretion, demonstrating liver-organ crosstalk via the circulatory system. Exogenous administration of ORM2 effectively ameliorates ferroptosis and tissue damage in multiple ischemia-reperfusion injury models. Collectively, our results identify the hepatokine ORM2 as a key suppressor of pathological ferritinophagy. This function positions ORM2 protein as a potential therapeutic candidate for acute tissue injuries driven by ferritinophagy-mediated iron overload.