S-Adenosylmethionine Inhibits Plasminogen-Activating Inhibitor-1 and Protects Male Mice From FOLFOX-Induced Liver...

Area of Science:

• Hepatology and Pharmacology
• Gastroenterology and Oncology
• Molecular and Cellular Biology

Background:

• FOLFOX chemotherapy commonly treats colorectal liver metastases but can induce sinusoidal obstruction syndrome (SOS), a form of liver toxicity that impedes further treatment.
• S-adenosylmethionine (SAMe) is recognized for its hepatoprotective properties.
• The protective effects of SAMe against FOLFOX-induced hepatotoxicity and its underlying molecular mechanisms remain to be fully elucidated.

Purpose of the Study:

• To investigate the protective potential of SAMe against FOLFOX-induced hepatotoxicity.
• To elucidate the molecular mechanisms by which SAMe exerts its hepatoprotective effects in the context of FOLFOX treatment.
• To define the role of plasminogen-activating inhibitor-1 (PAI-1) in FOLFOX-induced liver injury.

Main Methods:

• A murine model was utilized to study FOLFOX-induced SOS, examining the effects of SAMe and PAI-1.
• In vitro experiments involved primary mouse and human hepatocytes, Kupffer cells, hepatic stellate cells, and liver sinusoidal endothelial cells.
• Key molecular pathways, including nuclear factor-kappa B (NF-κB) activation and Serpine1 (encoding PAI-1) expression, were analyzed.

Main Results:

• SAMe cotreatment completely prevented the increase in SOS markers and protected against liver injury in the murine model.
• FOLFOX treatment upregulated Serpine1, encoding PAI-1, and SAMe inhibited FOLFOX-induced NF-κB activation, a key regulator of Serpine1.
• PAI-1 deficiency protected male mice from FOLFOX-induced liver injury and NF-κB activation; PAI-1 promoted inflammatory responses in hepatocytes and immune cells.

Conclusions:

• Hepatocyte PAI-1 expression, induced by FOLFOX, contributes to liver injury, an effect absent in PAI-1 deficient mice.
• Hepatocyte-derived PAI-1 mediates autocrine and paracrine signaling, activating Kupffer cells and liver sinusoidal endothelial cells.
• SAMe confers protection against FOLFOX-induced liver injury primarily by inhibiting NF-κB activation and subsequent PAI-1 induction.