Inhibition of the SerpinB3/protease-activated receptor 2 axis reduces liver cancer development and affects lipid metabolism

MASLD and HCC are increasing challenges in hepatology. 1-Piperidinepropionic acid (1-PPA), a protease-activated receptor 2 (PAR2) inhibitor, downregulates SerpinB3, a molecule involved in fibrosis and HCC. This study investigates the effects of 1-PPA on lipid accumulation and HCC development.

1-PPA was employed in primary hepatocytes and human liver organoids cultured with steatogenic compounds and lomitapide, a VLDL-formation inhibitor. Antitumoral effects of 1-PPA were evaluated by proliferation and invasion assays in HepG2 cells and in human liver organoids treated with a tumorigenic compound. MASH-related carcinogenesis was studied in vivo using C57BL/6J mice overexpressing SerpinB3 (C57/TG) and BALB/c mice deficient in the reactive site loop of Serpinb3a (BC/KO).

1-PPA reduced tumour development and steatosis in vivo. Proteomic analysis showed decreased lipid synthesis and deposition post-treatment. Suppression of lipid accumulation was favoured by an increase in VLDL export, supported by an enhanced microsomal triglyceride transfer protein activity in vivo and by a competitive effect between 1-PPA and lomitapide in vitro. The compound 1-PPA also exhibited direct antitumoral effects, reducing proliferation, survival and invasion in liver organoids and HepG2 cells.

1-PPA administration prevents lipid accumulation and HCC development in MASH-related liver carcinogenesis.

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The datasets analysed during the current study are available from the corresponding author on reasonable request. The data generated from the in vivo and in vitro models are available upon request from the corresponding author. The data analysis of human samples were obtain from cBioPortal.

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