Core Insights - The article discusses the increasing public health burden of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and its progression to Metabolic Dysfunction-Associated Steatohepatitis (MASH), highlighting limited treatment options [2] - A study published in Cell Metabolism reveals that the diene acid analog 326E alleviates MASH by dual targeting ACLY and PPARα, demonstrating its therapeutic potential and good tolerability in human clinical trials [2][5] Group 1: Mechanism and Efficacy - The diene acid ATP-citrate lyase (ACLY) inhibitor 326E significantly reduces liver lipid accumulation and alleviates MASH symptoms in mouse models [3] - 326E works by inhibiting ACLY to decrease de novo lipogenesis (DNL) and acts as an allosteric modulator of PPARα to enhance fatty acid oxidation (FAO), thus addressing MASH [3][8] - The study confirmed the preventive effects of 326E on MASH in non-human primates, further supporting its potential as a treatment [4] Group 2: Clinical Trials and Results - A randomized 1b/2a phase clinical trial in human MASH patients (NCT06491576) showed that 326E has good tolerability and lowers levels of γ-glutamyl transferase (γ-GGT), a key biomarker for liver disease [5][9] - The results from preclinical studies in mice and non-human primates, along with human clinical trials, indicate that 326E has therapeutic potential for MASH through its unique mechanisms of action [8]