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

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.