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PAD4⁺ Neutrophils Promote Hepatic Stellate Cell Activation and Accelerate MASH Fibrosis Progression via NETs-DNA/TAOK1/MAPK Pathways

GSE308064 Homo sapiens Expression profiling by high throughput sequencing 6 samples Submitted 2025/11/07 Platform GPL23227
Summary
Neutrophils play a pivotal role in the progression of metabolic-associated steatohepatitis (MASH) by mediating inflammatory responses. However, the heterogeneity of neutrophil subsets in MASH and their specific contributions to disease progression remain unclear. In this study, analysis of liver biopsies from 265 patients revealed a strong association between elevated neutrophil counts and MASH severity, particularly fibrosis. Five distinct neutrophil subsets were identified in human liver tissue, with PAD4⁺ neutrophils serving as key drivers in MASH progression. Mechanistically, PAD4⁺ neutrophils generate neutrophil extracellular traps (NETs) and activate hepatic stellate cells via the TAOK1-dependent MAPK signaling pathway. Inhibition of PAD4⁺ neutrophils in vivo attenuated the progression of liver fibrosis without exacerbating liver injury. Collectively, these findings elucidate the pivotal involvement of PAD4⁺ neutrophils in MASH progression and identify them as promising therapeutic targets for mitigating fibrosis and inflammation.
Published in
PAD4+ neutrophils promote hepatic stellate cell activation and accelerate MASH fibrosis progression viaNET-DNA/TAOK1/MAPK pathways
Shen J, Huang S, Wang Y et al. · JCI insight 2026 · PMID 41480748 · doi:10.1172/jci.insight.191479
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Also filed as BioProject PRJNA1072289 and SRA study SRP487670. Searching any of these in the dataset finder brings you back here.

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