Hyperinflammatory Reprogramming Marks the Transition from MASH to HCC.

Authors

Shawn Lu Wen Tan, Erez Israeli, Jillian Wee, Hui Min Tan, Ravisankar Rajarethinam, Immanuel Kwok, Shu Zhen Chong, Weiping Han

Published in

JHEP reports : innovation in hepatology. Pages 102055. Oct 07, 2026. Epub Oct 07, 2026.

Abstract

Up to 40% of metabolic dysfunction-associated steatohepatitis (MASH)-associated hepatocellular carcinoma (HCC) occurs in the absence of cirrhosis. Yet the biological features that underlie non-cirrhotic MASH-to-HCC progression remain poorly understood. We sought to define the cellular and molecular programs associated with non-cirrhotic MASH-to-HCC progression.
We integrated histopathological and biochemical assessments, bulk and single-cell RNA sequencing, serum cytokine profiling, and multiplex immunohistochemistry in Gubra-Amylin-NASH diet-fed mice that remained HCC-naïve or developed non-cirrhotic HCC. Key findings were evaluated in an independent human cohort of non-cirrhotic MASH and MASH-HCC.
Body composition metrics, fibrosis severity, histopathology and liver injury markers poorly distinguished HCC-progressors from non-progressors. In contrast, bulk transcriptomics identified prominent immune dysregulation in cancer-primed adjacent non-tumor liver. Single-cell RNA-sequencing revealed coordinated hyperinflammatory reprogramming characterized by loss of Trem2⁺ macrophages, expansion of Trem2^low pro-inflammatory macrophages, immature neutrophil accumulation, T helper 17 skewing and heightened activation of dendritic and endothelial cells. Cell-cell communication analysis identified IL-1 as the most altered signaling pathway in HCC-progressors (pathway distance = 7.95, top-ranked), with myeloid-derived IL-1β signaling emerging as a dominant axis targeting endothelial and immune populations. Elevated circulating IL-6 (154.3 vs. 30.1 pg/ml, p =0.065) and TNF (25.2 vs. 16.0 pg/ml, p =0.062) in HCC-progressors support a systemic hyperinflammatory phenotype. Human non-cirrhotic MASH-HCC adjacent non-tumor tissues similarly exhibited increased IL1B expression (log₂ expression = 4.21 vs. 4.03, p <0.01) and enrichment of IL-1β-responsive inflammatory programs.
Non-cirrhotic MASH-to-HCC progression is associated with coordinated hyperinflammatory reprogramming across immune and stromal compartments. Myeloid-derived IL-1β is a central signaling axis within the cancer-permissive MASH microenvironment, providing a potential basis for HCC risk stratification and preventive intervention.

PMID:
42843561
Bibliographic data and abstract were imported from PubMed on 08 Oct 2026.

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