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

Area of Science:

• Hepatology
• Oncology
• Biochemistry

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC) present growing clinical challenges.
• 1-Piperidinepropionic acid (1-PPA), a protease-activated receptor 2 (PAR2) inhibitor, downregulates SerpinB3, a key mediator in liver fibrosis and HCC.
• This research explores 1-PPA's therapeutic potential in mitigating lipid accumulation and HCC progression.

Purpose of the Study:

• To investigate the efficacy of 1-PPA in reducing lipid accumulation in liver cells.
• To evaluate the antitumoral effects of 1-PPA on HCC development in preclinical models.
• To elucidate the mechanisms by which 1-PPA influences lipid metabolism and liver carcinogenesis.

Main Methods:

• 1-PPA was tested in primary hepatocytes and human liver organoids exposed to steatogenic conditions and lomitapide.
• Antitumoral activities were assessed via proliferation and invasion assays in HepG2 cells and liver organoids.
• MASH-related carcinogenesis models involved C57BL/6J mice overexpressing SerpinB3 and BALB/c mice deficient in Serpinb3a.

Main Results:

• 1-PPA significantly reduced tumor development and steatosis in vivo.
• Proteomic analysis revealed decreased lipid synthesis and deposition, alongside enhanced VLDL export.
• 1-PPA demonstrated direct antitumoral effects, inhibiting proliferation, survival, and invasion in liver cells and organoids.

Conclusions:

• 1-PPA administration effectively prevents lipid accumulation and HCC development in the context of MASH-related liver carcinogenesis.
• The findings highlight 1-PPA as a potential therapeutic agent for MASLD and associated HCC.