Hepatic IFRD1 suppresses metabolic dysfunction-associated steatohepatitis via GLUD1/α-KG axis (IMAGE)
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Graphical abstract: In healthy livers, IFRD1 directly binds to GLUD1, facilitating GLUD1 mitochondrial localization and sustaining its enzymatic activity to continuously generate α-KG. α-KG suppresses hepatic de novo lipogenesis (DNL) by reducing the enrichment of H3K36me3 at lipogenic gene loci. In MASLD-affected livers, IFRD1 expression is downregulated, weakening its interaction with GLUD1. This leads to diminished GLUD1 enzymatic activity and reduced α-KG production. Elevated H3K36me3 accumulation across lipogenic gene regions subsequently activates the DNL pathway and exacerbates pathological damage of MASLD. Hepatocyte-specific overexpression of IFRD1 reverses the above pathological cascade and alleviates MASLD progression via activating the GLUD1-α-KG-H3K36me3 regulatory axis.
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