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Hepatocellular carcinoma (HCC) and Metabolic-Associated Steatohepatitis (MASH) are major challenges in modern hepatology. 1-Piperidinepropionic Acid (1-PPA) is a novel inhibitor of Protease-Activated Receptor 2 (PAR2), which is involved in inflammation, lipid accumulation and tumour development. This study aims to evaluate the effect of 1-PPA on liver steatosis, inflammation and HCC development. C57BL/6J mice transgenic overexpressing SerpinB3 (C57/TG), fed on a CDAA diet and injected with diethylnitrosamine (DEN) were divided into two groups (n=8 each) and treated with 1-PPA or placebo. HCC development was confirmed by liver histology. Microsomal triglyceride transfer protein (MTP) activity was quantified in liver tissue using a specific assay. qPCR of macrophage M2-polarization markers was carried out. Human liver organoids were cultured with Oleic Acid and SB3, and treated with 1-PPA and lomitapide, an inhibitor of VLDL export. Lipid and ROS accumulation was quantified using BodiPY and MitoSOX respectively. C57/TG mice treated with 1-PPA developed a lower mean number of nodules (1.5 vs 5, p < 0.05), a reduced mean tumoral mass (0.04 vs 0.1 g, p < 0.01) and a blunted expression of M2-polarization macrophage markers. MTP activity was increased in the liver of mice treated with 1-PPA. Human liver organoids showed a significant increase in lipid and ROS accumulation after Oleic Acid administration. Treatment with 1-PPA significantly lower lipid and ROS accumulation, however contemporary treatment with lomitapide reverted this effect, suggesting a role in VLDL export. 1-PPA treatment reduced HCC development by reducing lipid accumulation and M2-macrophage polarization in a mouse model of NASH-induced liver carcinogenesis. 1-PPA treatment reduced lipid accumulation by stimulating VLDL formation and secretion both in a mouse model of MASH-induced liver carcinogenesis and in human liver organoids. [ABSTRACT FROM AUTHOR]