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

Summary

Human MASH livers show marked increases in neutrophil proteases NE and PR3 that correlate with histologic severity. Genetic deletion or AAV-mediated inhibition of NE/PR3 mitigated steatohepatitis and fibrosis in mice, while miR-223 suppresses NE/PR3 via STAT3; miR-223 deficiency exacerbated disease. Bone marrow chimerism experiments indicate hematopoietic miR-223 regulates hepatic NE/PR3 and fibrosis progression.

Key Findings

• NE and PR3 were markedly increased in human MASH/fibrotic livers and correlated with histology.
• Genetic ablation or AAV-mediated inhibition of NE/PR3 reduced steatohepatitis and fibrosis in mice.
• miR-223 suppressed neutrophilic NE/PR3 by targeting STAT3; miR-223 deficiency worsened inflammation/fibrosis.
• Bone marrow transplantation generating miR-223 chimerism modulated hepatic NE/PR3 and MASH fibrosis progression.

Clinical Implications

Supports development of NE/PR3 inhibitors and strategies to boost miR-223 signaling as potential anti-fibrotic therapies in MASH. Biomarker work on NE/PR3 could inform risk stratification.

Limitations

• Predominantly preclinical efficacy; no human interventional data yet.
• Diet-induced mouse models may not capture full MASLD/MASH heterogeneity.

Future Directions

Test NE/PR3 inhibitors or miR-223–modulating therapies in clinically relevant models and early-phase trials; validate NE/PR3 as biomarkers for activity and response.