The study investigates the therapeutic potential of PHAR, a protein-protein interaction inhibitor targeting the NRF2/β-TrCP axis, in non-alcoholic steatohepatitis (NASH) and its progression to fibrosis. PHAR was found to activate NRF2 in hepatocytes, Kupffer cells, and stellate cells, leading to a reduction in liver fat accumulation, inflammation, and fibrosis. In the STAM mouse model of NASH, PHAR treatment significantly reduced steatosis, hepatocellular ballooning, and inflammation, as well as decreased the expression of pro-fibrotic and inflammatory genes. The study suggests that mild activation of NRF2 via PHAR holds promise as a strategy for addressing NASH and its progression to liver fibrosis.The study investigates the therapeutic potential of PHAR, a protein-protein interaction inhibitor targeting the NRF2/β-TrCP axis, in non-alcoholic steatohepatitis (NASH) and its progression to fibrosis. PHAR was found to activate NRF2 in hepatocytes, Kupffer cells, and stellate cells, leading to a reduction in liver fat accumulation, inflammation, and fibrosis. In the STAM mouse model of NASH, PHAR treatment significantly reduced steatosis, hepatocellular ballooning, and inflammation, as well as decreased the expression of pro-fibrotic and inflammatory genes. The study suggests that mild activation of NRF2 via PHAR holds promise as a strategy for addressing NASH and its progression to liver fibrosis.