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Background <p>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.</p> Methods <p>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).</p> Results <p>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.</p> Conclusions <p>1-PPA administration prevents lipid accumulation and HCC development in MASH-related liver carcinogenesis.</p> <p></p>

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

  • 期刊论文

  • 发表日期：

    2026年4月22日

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  • Pietro Guerra,
  • Gianmarco Villano,
  • Claudia M. Rejano-Gordillo,
  • Clàudia Gil-Pitarch,
  • Mariagrazia Ruvoletto,
  • Alessandra Biasiolo,
  • Santina Quarta,
  • L. Estefanía Zapata-Pavas,
  • Patricia Peña-SanFelix,
  • Irene González-Recio,
  • Naroa Goikoetxea-Usandizaga,
  • Jon Ander Barrenechea-Barrenechea,
  • Arantza Sanz-Parra,
  • Alessandro Gambella,
  • Silvia De Siervi,
  • Barbara Oliviero,
  • Stefania Mantovani,
  • Jessica Nurcis,
  • Silvia Cagnin,
  • Andrea Martini,
  • Cristian Turato,
  • Stefania Cannito,
  • Maria Guido,
  • Maurizio Parola,
  • María Luz Martínez-Chantar,
  • Patrizia Pontisso

摘要

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.