MASH-in-a-dish reveals fatty acid-driven itaconate crosstalk between Kupffer cells and hepatocytes

Fatty acids drive Kupffer cell itaconate production via the carnitine shuttle in MASH-in-a-dish, aggravating oxidative stress, steatosis, and cell damage in lipid-stressed hepatocyte organoids.

• Why it matters: Metabolite signaling between liver cell types is central to MASH progression, but separating cell-specific metabolite crosstalk in diseased liver tissue is difficult.
• What they did: The study built a Transwell “MASH-in-a-dish” co-culture of mouse HepOrgs, Kupffer cells, and hepatic stellate cells in a defined medium, then used cell-type-specific metabolomics and stable-isotope fluxomics to find 19 MASH-associated, interaction-responsive metabolites.
• The result: KC-specific Acod1 knockout, which inhibits itaconate production in this system, mitigated hepatocyte damage, supporting itaconate crosstalk as a pathogenic mechanism and therapeutic target in MASH.

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