Nintedanib attenuates NLRP3 inflammasome-driven liver fibrosis by targeting Src signaling

Area of Science:

• Hepatology and immunology
• Pharmacology and drug discovery

Background:

• Liver injury triggers inflammation and hepatic stellate cell activation, initiating liver fibrosis.
• Nintedanib, a tyrosine kinase inhibitor, is approved for idiopathic pulmonary fibrosis but its role in liver fibrosis is unclear.
• The inflammasome pathway, particularly NLRP3, is implicated in liver fibrosis pathogenesis.

Purpose of the Study:

• To investigate the anti-fibrotic efficacy of nintedanib in a carbon tetrachloride-induced liver fibrosis model.
• To evaluate nintedanib's effect on nucleotide oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in vitro.
• To explore nintedanib's molecular targets, including the Src signaling pathway, in liver fibrosis.

Main Methods:

• A carbon tetrachloride (CCl4)-induced liver fibrosis model in vivo.
• Activation of NLRP3 inflammasomes in LX-2 cells using lipopolysaccharide and ATP.
• Assessment of nintedanib's effects on inflammasome activation, Src signaling, and fibrotic markers.
• Use of lentiviruses to manipulate Src expression in LX-2 cells.

Main Results:

• Nintedanib attenuated liver inflammation and extracellular matrix accumulation in fibrotic livers.
• Nintedanib reduced the expression of NLRP3, fibrotic markers, and phosphorylation of Src, EGFR, AKT, and ERK1/2 in LX-2 cells.
• Nintedanib inhibited NLRP3 inflammasome activation by suppressing Src phosphorylation, downstream signaling, and reactive oxygen species production.

Conclusions:

• Nintedanib demonstrates significant anti-fibrotic effects in a preclinical model.
• Nintedanib effectively suppresses NLRP3 inflammasome activation, a key driver of liver fibrosis.
• Nintedanib holds potential as a therapeutic agent for liver fibrosis treatment.