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<p>Metabolically-dysfunction-associated steatohepatitis (MASH) is characterised by embryonic Kupffer cell (emKC) loss and proinflammatory macrophage infiltration. While iron dysregulation is implicated in MASH, the role of labile iron (Fe2 + ) in mediating emKC survival and function remains unknown. In human and mouse MASLD/MASH livers, emKCs exhibit repressed iron metabolism, reduced labile iron pools, and mitochondrial dysfunction. KC-specific ferroportin knockout mice recapitulate these defects, accelerating Western diet-induced steatosis and fibrosis. Conversely, ferritin depletion restores emKC labile iron levels, mitigates mitochondrial damage, and attenuates disease severity. Fe2+ deficiency blunts Trem2 expression, whereas restoring Fe2+ homeostasis elevates emKC Trem2 abundance in MASH liver. Weight loss reverses hepatic iron dysfunction and restores emKC homeostasis. Our findings establish labile iron deficiency as a key driver of emKC loss and functional switch in MASH, linking iron metabolism to mitochondrial fitness and inflammation. Targeting emKC iron homeostasis could offer novel therapeutic strategies for MASLD/MASH.</p>

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Labile iron starvation in embryonic Kupffer cells aggravates MASH via mitochondrial failure and macrophage dysfunction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Ke Wang,
  • Garam An,
  • Junho Park,
  • Karina Cunha e Rocha,
  • Zixuan Zeng,
  • Houji Qin,
  • Andrea Farrell,
  • Alex Schlotthauer,
  • Whasun Lim,
  • Wei Ying

摘要

Metabolically-dysfunction-associated steatohepatitis (MASH) is characterised by embryonic Kupffer cell (emKC) loss and proinflammatory macrophage infiltration. While iron dysregulation is implicated in MASH, the role of labile iron (Fe2 + ) in mediating emKC survival and function remains unknown. In human and mouse MASLD/MASH livers, emKCs exhibit repressed iron metabolism, reduced labile iron pools, and mitochondrial dysfunction. KC-specific ferroportin knockout mice recapitulate these defects, accelerating Western diet-induced steatosis and fibrosis. Conversely, ferritin depletion restores emKC labile iron levels, mitigates mitochondrial damage, and attenuates disease severity. Fe2+ deficiency blunts Trem2 expression, whereas restoring Fe2+ homeostasis elevates emKC Trem2 abundance in MASH liver. Weight loss reverses hepatic iron dysfunction and restores emKC homeostasis. Our findings establish labile iron deficiency as a key driver of emKC loss and functional switch in MASH, linking iron metabolism to mitochondrial fitness and inflammation. Targeting emKC iron homeostasis could offer novel therapeutic strategies for MASLD/MASH.