2. Academic Validation
  3. C/EBPβ-VCAM1 axis in Kupffer cells promotes hepatic inflammation in MASLD

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

  • JHEP Rep. 2025 Apr 15;7(8):101418. doi: 10.1016/j.jhepr.2025.101418.
Shuang-Zhe Lin 1,  Yang Xie 1,  Yu-Qing Cheng 1,  Rui Xue 1,  Yin-Shi Su 2,  Mingxi Liu 3,  Yuan-Wen Chen 2 4,  Jian-Gao Fan 1 5
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai, China.
  • 3 State Key Laboratory of Reproductive Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
  • 4 Department of Gerontology, Huadong Hospital, Fudan University, Shanghai, China.
  • 5 Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
PMID: 40677688 DOI: 10.1016/j.jhepr.2025.101418
Abstract

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 Cebpb heterozygous knockout mice (n = 10 per group), followed by liver evaluation using histopathology, flow cytometry, and RNA-seq. RNA-seq of liver tissue (n = 3 per group) and C/EBPβ CUT&Tag-seq of sorted KCs were comprehensively analyzed to elucidate the transcriptional regulatory network. Flow cytometry and immunofluorescence were used to detect the expression or distribution of key proteins.

Results: HFHCD induced prominent immune cell infiltration and a concomitant increase in C/EBPβ in KCs. KC-specific Cebpb heterozygous knockout significantly reduced HFHCD-induced lobular inflammation (p <0.05) and inflammation-related gene expression (p <0.05) in the liver. Multi-omics analysis revealed increased C/EBPβ activity in KCs in MASLD, leading to a selective promotive effect on MASLD-induced genes. Further integrated analysis identified Vcam1 as a key direct downstream gene of C/EBPβ in KCs in MASLD, which involves C/EBPβ-mediated activation of the Vcam1 promoter. VCAM1 was predominantly expressed in KCs in the hepatic tissue of MASLD mice and patients. KC-expressed VCAM1 was significantly increased in MASLD compared with healthy controls (p <0.01), and it promoted immune cell infiltration into the liver.

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.

Keywords

C/EBPβ; Kupffer cell; MASH; MASLD; VCAM1.

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