The OGT-TFF2 axis mediates intrahepatic crosstalk and MASH pathogenesis.

BACKGROUND AND AIMS: Metabolic dysfunction-associated fatty liver disease (MASLD) encompasses a spectrum of liver pathologies ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. The mechanisms governing disease progression, particularly the communication between hepatocytes and non-parenchymal cells, remain poorly understood. In this study, we demonstrate a novel paracrine factor through which O‑GlcNAc transferase (OGT) regulates intercellular crosstalk between hepatocytes and immune cells in MASH development. APPROACH AND RESULTS: OGT and trefoil factor 2 (TFF2) expression were analyzed in human and mouse livers. The effects of the paracrine factor on inflammation and fibrogenesis were further evaluated in a 3D mouse liver spheroid model of MASH. The GalNAc-modified siRNA targeting the paracrine factor was applied in Gubra-Amylin NASH (GAN) diet-fed mice to determine its therapeutic potential in preventing the MASH progression. Decreased OGT expression during MASLD promotes TFF2 transcription and secretion via forkhead box protein A2 (FOXA2) modulation. In 3D mouse liver spheroids, TFF2 exacerbates MASH-related pathologies. Mechanistically, TFF2 enhances hepatic CD4+ T cell proliferation and Th1/Th17 differentiation through CXC motif chemokine receptor 4 (CXCR4)-signal transducer and activator of transcription 1/3 (STAT1/3) signaling, cooperating with CXC motif chemokine ligand 12 (CXCL12) to amplify inflammation. Hepatocyte-specific Tff2 inhibition using GalNAc-modified siRNA in a diet-induced mouse model ameliorates MASH progression without affecting simple steatosis development. CONCLUSIONS: These results identify an OGT-TFF2 axis that mediates the crosstalk between hepatocytes and CD4 T cells during MASH pathogenesis, revealing a potential therapeutic target for the treatment of chronic liver disease.