Neutrophil serine proteases NE and PR3 controlled by the miR-223/STAT3 axis potentiate MASH and liver fibrosis

作者：Pengfei Zhang, Dongyang Liu, Lihong Wu, Xiaoqin Wu, Kaixuan Yan, Mengqi Fan, Danqi Zou, Erfei Song, Yumeng Jiang, Ying Xu, Xiaoping Wu, Shufei Zang, Fei Zhu, Yuqi Chen, Zhikang Cen, Mengyao Bi, Yuying Zhang, Xicheng Wang, Wei Liu, Rongxin Zhang, Cunchuan Wang, Ruby L.C. Hoo, Aimin Xu, Dewei Ye · 发表于：Hepatology · 年份：2025 · DOI：10.1097/hep.0000000000001309 · 被引用次数：10 · 研究领域：Liver Disease Diagnosis and Treatment、Liver physiology and pathology、Liver Diseases and Immunity

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) and its related liver fibrosis represent a substantial public health burden with limited treatment options. Although MASH is associated with enhanced neutrophil infiltration in the liver, the mediators and mechanisms underlying neutrophil-driven progression of MASH and fibrosis remain largely unknown. This study aimed to investigate the role of neutrophil serine proteases neutrophil elastase (NE) and proteinase 3 (PR3) in the development of MASH and fibrosis. APPROACH AND RESULTS: Liver biopsies from 121 morbidly obese patients were recruited for analysis. NE -/- , PR3 -/- , microRNA-223 (miR-223) -/- mice and their wild-type controls were fed a choline-deficient, l -amino acid-defined, high-fat diet to induce MASH fibrosis. Bone marrow transplantation was performed to generate mice with miR-223 chimerism in bone marrow-derived cells. NE and PR3 content in the human liver with MASH and fibrosis was markedly increased in close association with histological features. Genetic ablation or adeno-associated virus-mediated inhibition of NE and PR3 substantially alleviated MASH and liver fibrosis in mice. A mechanistic study revealed that miR-223 suppressed neutrophilic NE and PR3 by targeting signal transducer and activator of transcription 3. MiR-223 deficiency augmented inflammation and fibrosis in mouse liver. Bone marrow transplantation-induced miR-223 chimerism significantly affected hepatic NE/PR3 con...