C/EBPβ-VCAM1 axis in Kupffer cells promotes hepatic inflammation in MASLD.

Background & Aims: Kupffer cells (KCs) can promote hepatic inflammation in metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying molecular mechanisms are not fully understood. C/EBPβ in macrophages can mediate metabolic and immune dysregulations. Therefore, we aimed to explore its role in KCs in MASLD pathogenesis. Methods: A 12-week high-fat and high-cholesterol diet (HFHCD) model was used in wild-type or KC-specific Results: HFHCD induced prominent immune cell infiltration and a concomitant increase in C/EBPβ in KCs. KC-specific Conclusions: Increased C/EBPβ in KCs promotes pathogenic transcriptional activation, leading to increased VCAM1 expression and inflammatory cell infiltration in MASLD. Inhibition of C/EBPβ in KCs might be a potential therapeutic strategy against hepatic inflammation in MASLD. Impact and implications: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, but its pathogenesis remains elusive. In this study, we investigated the critical role of CCAAT/enhancer binding protein β (C/EBPβ) in Kupffer cells and its implications in MASLD pathogenesis. We found that an increased C/EBPβ level in Kupffer cells promotes hepatic inflammation in MASLD by upregulating VCAM1 expression. Our findings provide valuable insights into the molecular mechanisms driving MASLD and propose a potential novel therapeutic target to mitigate hepatic inflammation in MASLD.