SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis

Fibrosis and organ failure is a common endpoint for many chronicliver diseases. Much is known about the upstream inflammatorymechanisms provoking fibrosis and downstream potential fortissue remodeling. However, less is known about the transcrip-tional regulationin vivogoverning fibrotic matrix deposition byliver myofibroblasts. This gap in understanding has hamperedmolecular predictions of disease severity and clinical progressionand restricted targets for antifibrotic drug development. In thisstudy, we show the prevalence of SOX9in biopsies from patientswith chronic liver disease correlated with fibrosis severity andaccurately predicted disease progression toward cirrhosis. Inacti-vation ofSox9in mice protected against both parenchymal andbiliary fibrosis, and improved liver function and amelioratedchronic inflammation. SOX9was downstream of mechanosignalingfactor, YAP1. These data demonstrate a role for SOX9in liverfibrosis and open the way for the transcription factor and itsdependent pathways as new diagnostic, prognostic, and therapeu-tic targets in patients with liver fibrosis.