Inhibition of the SerpinB3/protease-activated receptor 2 axis reduces liver cancer development and affects lipid metabolism
Menée à l'aide de lignées cellulaires, d'organoïdes et de modèles murins de carcinogenèse hépatique liée à une stéatohépatite associée à un dysfonctionnement métabolique, cette étude démontre que l'inhibition de l'axe impliquant la serpine B3 et le récepteur activé par les protéases 2 réduit le développement tumoral et affecte le métabolisme des lipides
Background : 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.
Methods : 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).
Results : 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.
Conclusions : 1-PPA administration prevents lipid accumulation and HCC development in MASH-related liver carcinogenesis.
British Journal of Cancer , article en libre accès, 2026