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Published on: March 16, 2018

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

Ke Wang1,2, Garam An1,3, Junho Park1,3

  • 1Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, CA, USA.

Cell Death & Disease
|June 17, 2026
PubMed

Insights

Labile iron deficiency drives loss of embryonic Kupffer cells in metabolic dysfunction-associated steatohepatitis (MASH). Restoring iron homeostasis in these cells may offer new MASH therapies.

Area of Science:

  • Hepatology
  • Immunology
  • Metabolic Diseases

Background:

  • Metabolic dysfunction-associated steatohepatitis (MASH) involves embryonic Kupffer cell (emKC) loss and inflammation.
  • Iron dysregulation is linked to MASH, but the role of labile iron (Fe2+) in emKC function is unclear.

Purpose of the Study:

  • Investigate the role of labile iron (Fe2+) in emKC survival and function in MASH.
  • Determine if targeting emKC iron homeostasis can be a therapeutic strategy for MASH.

Main Methods:

  • Analysis of human and mouse MASH livers for emKC iron metabolism and mitochondrial function.
  • Utilized KC-specific ferroportin knockout mice and ferritin depletion models.
  • Assessed Trem2 expression and effects of weight loss on hepatic iron.

Main Results:

  • MASH livers show repressed emKC iron metabolism, reduced labile iron, and mitochondrial dysfunction.
  • KC-specific ferroportin knockout accelerated MASH progression; ferritin depletion improved emKC function and reduced disease severity.
  • Fe2+ deficiency decreased Trem2 expression, while iron restoration increased it; weight loss normalized emKC iron homeostasis.

Conclusions:

  • Labile iron deficiency is a key factor in emKC loss and dysfunction in MASH.
  • Iron metabolism is intrinsically linked to mitochondrial health and inflammation in MASH.
  • Modulating emKC iron homeostasis presents a potential therapeutic avenue for MASH.

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