Neutrophil extracellular traps-triggered hepatocellular senescence exacerbates lipotoxicity in non-alcoholic steatohepatitis.

Abstract

INTRODUCTION: Neutrophils are initial responders in inflammation and contribute to non-alcoholic fatty liver disease (NAFLD) progression to steatohepatitis (NASH). Neutrophil extracellular traps (NETs) are implicated in liver injury, yet their precise mechanisms in NASH progression remains unclear. OBJECTIVES: This study investigates how NETs drive NASH progression by exacerbating hepatocyte lipotoxicity and explore the regulatory mechanism of NETs formation and its downstream effects on liver pathology. METHODS: Clinical samples from NASH patients and diet-induced NASH mice were analyzed for NET levels. NETs were pharmacologically inhibited, and senescent cells were selectively eliminated in mice. Myeloid-specific RBP-J knockout mice were generated to disrupt Notch signaling, with subsequent evaluation of NET formation, senescence markers, steatosis, fibrosis, and inflammation. RESULTS: NETs were elevated in NASH patients and mice, correlating with hepatocyte senescence and lipotoxicity. Pharmacological NET disruption reduced hepatocyte senescence, accompanied by attenuated steatosis and fibrosis. Senescent cell clearance replicated these improvements, confirming liver senescence emerges is a vital step for NETs to promote the progression of NASH. Myeloid-specific Notch signaling ablation suppressed NET generation, concurrently decreasing lipid deposition and liver inflammation. CONCLUSION: Our findings elucidate a novel mechanism by which neutrophil-derived Notch driven NETs exacerbate NASH by promoting cell senescence, thereby contributing to hepatic steatosis and fibrosis. This insight may provide potential intervention strategies and therapeutic targets for NASH treatment.