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

Abstract Background Liver injury induces an inflammatory response that activates hepatic stellate cells, which is the initial factor of liver fibrosis. Nintedanib, a multi-targeted tyrosine kinase inhibitor targeting the Src signaling pathway, has been approved for the treatment of idiopathic pulmonary fibrosis. However, it is still not known whether nintedanib ameliorates liver fibrosis by inhibiting inflammasome activation. Methods A carbon tetrachloride (CCl4)-induced liver fibrosis model was used to assess the anti-fibrotic efficacy of nintedanib in vivo. Lipopolysaccharide and ATP were used to activate nucleotide oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in LX-2 cells, and the efficacy of nintedanib on NLRP3 inflammasome activation was evaluated. Moreover, we used Src-overexpressing and Src-downregulating lentiviruses to transfect LX-2 cells to explore the targets of nintedanib. Results Nintedanib attenuated inflammation and extracellular matrix accumulation in CCl4-induced fibrotic livers and reduced the expression of NLRP3, fibrotic makers, the phosphorylation of Src, epidermal growth factor receptor, AKT and ERK1/2 in LX-2 cells, and nintedanib thwarted NLRP3 inflammasome activation via suppressing the phosphorylation of Src and its downstream signaling pathway and reactive oxygen species. Conclusions Our study indicates that nintedanib effectively suppresses NLRP3 inflammasome activation and has the potential for the treatment of liver fibrosis. Keywords: Nintedanib, liver fibrosis, hepatic stellate cell, Src, NLRP3 inflammasome