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While iron dysregulation is implicated in MASH, the role of labile iron (Fe2\u2009+\u2009) 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.<\/jats:p>","DOI":"10.1038\/s41419-026-08985-7","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T23:33:22Z","timestamp":1781739202000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Labile iron starvation in embryonic Kupffer cells aggravates MASH via mitochondrial failure and macrophage dysfunction"],"prefix":"10.1038","volume":"17","author":[{"given":"Ke","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garam","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junho","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"Cunha e Rocha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6420-7098","authenticated-orcid":false,"given":"Zixuan","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houji","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Farrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7211-1393","authenticated-orcid":false,"given":"Alex","family":"Schlotthauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1328-0465","authenticated-orcid":false,"given":"Whasun","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4890-7256","authenticated-orcid":false,"given":"Wei","family":"Ying","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"8985_CR1","doi-asserted-by":"crossref","unstructured":"Yu J, Shen J, Sun TT, Zhang X, Wong N, editors. 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