The study explores the therapeutic potential of targeting the NRF2/β-TrCP axis to treat non-alcoholic steatohepatitis (NASH) and its progression to liver fibrosis. PHAR, a protein-protein interaction inhibitor of the NRF2/β-TrCP complex, was tested in the STAM mouse model of NASH, which mimics human NASH and fibrosis. PHAR was found to activate NRF2 in hepatocytes, Kupffer cells, and stellate cells, leading to reduced liver fat accumulation, inflammation, and fibrosis. Transcriptomic analysis revealed that PHAR upregulated anti-fibrotic genes (Plg, Serpina1a, Bmp7) and downregulated pro-fibrotic genes (Acta2, Col3a1), extracellular matrix remodeling genes, and inflammatory genes. PHAR also reduced oxidative stress markers, such as reduced glutathione (GSH) and lipid peroxidation products. The study demonstrated that PHAR is safe for prolonged administration in mice, with no significant toxicity or weight loss. PHAR significantly protected against NASH progression, including fibrosis, and improved liver histology. The results suggest that mild activation of NRF2 via PHAR could be a promising strategy for treating NASH and its progression to liver fibrosis.The study explores the therapeutic potential of targeting the NRF2/β-TrCP axis to treat non-alcoholic steatohepatitis (NASH) and its progression to liver fibrosis. PHAR, a protein-protein interaction inhibitor of the NRF2/β-TrCP complex, was tested in the STAM mouse model of NASH, which mimics human NASH and fibrosis. PHAR was found to activate NRF2 in hepatocytes, Kupffer cells, and stellate cells, leading to reduced liver fat accumulation, inflammation, and fibrosis. Transcriptomic analysis revealed that PHAR upregulated anti-fibrotic genes (Plg, Serpina1a, Bmp7) and downregulated pro-fibrotic genes (Acta2, Col3a1), extracellular matrix remodeling genes, and inflammatory genes. PHAR also reduced oxidative stress markers, such as reduced glutathione (GSH) and lipid peroxidation products. The study demonstrated that PHAR is safe for prolonged administration in mice, with no significant toxicity or weight loss. PHAR significantly protected against NASH progression, including fibrosis, and improved liver histology. The results suggest that mild activation of NRF2 via PHAR could be a promising strategy for treating NASH and its progression to liver fibrosis.