Lactylation of lysine396 in TNFRSF25 by lysine acetyltransferase 6B aggravates ferroptosis in metabolic dysfunction–associated steatohepatitis

BACKGROUND AND PURPOSE: Metabolic dysfunction-associated steatohepatitis (MASH) is a severe clinical complication of metabolic syndrome, but effective pharmacological treatments remain scarce. This study investigated the role of lactylation-a novel post-translational modification-in the pathogenesis of MASH, using murine models. EXPERIMENTAL APPROACH: RNA sequencing was employed to identify lactylation-associated regulators in a murine model of metabolic dysfunction-associated fatty liver disease (MAFLD) The functional role of the lysine acetyltransferase 6B (Kat6B) was validated through assays measuring intracellular glutathione levels, lipid accumulation and ferroptosis markers. Furthermore, the specific lactylation site on the downstream target was identified using mass spectrometry. KEY RESULTS: The lysine acetyltransferase Kat6B emerged as the most significantly dysregulated lactyltransferase in our murine model of MAFLD. Its overexpression induced a paradoxical increase in glutathione levels, alongside aggravated steatosis and ferroptosis. Mechanistically, Kat6B catalysed the lactylation of the TNF receptor TNFRSF25, at its lysine396 (K396) residue. CONCLUSIONS AND IMPLICATIONS: These findings define a lactic acid-driven pathogenic axis, in which the lactylation of TNFRSF25, mediated by Kat6B, exacerbated the progression of MASH, through promoting ferroptosis. Targeting this pathway may offer a novel therapeutic strategy for metabolic liver disease.