Dual TBK1/IKKɛ inhibitor amlexanox attenuates the severity of hepatotoxin‐induced liver fibrosis and biliary fibrosis in mice

Abstract

Although numerous studies have suggested that canonical IκB kinases (IKK) play a key role in the progression of liver fibrosis, the role of non-canonical IKKε and TANKbinding kinase 1 (TBK1) on the development and progression of liver fibrosis remains unclear. To demonstrate such issue, repeated injection of CCl 4 was used to induce hepatotoxin-mediated chronic liver injury and biliary fibrosis was induced by 0.1% diethoxycarbonyl-1, 4-dihydrocollidine diet feeding for 4 weeks. Mice were orally administered with amlexanox (25, 50, and 100 mg/kg) during experimental period.Significantly increased levels of TBK1 and IKKε were observed in fibrotic livers or hepatic stellate cells (HSCs) isolated from fibrotic livers. Interestingly, amlexanox treatment significantly inhibited the phosphorylation of TBK1 and IKKε accompanied by reduced liver injury as confirmed by histopathologic analysis, decreased serum biochemical levels and fibro-inflammatory responses. Additionally, treatment of amlexanox promoted the fibrosis resolution. In accordance with these findings, amlexanox treatment suppressed HSC activation and its related fibrogenic responses by partially inhibiting signal transducer and activator of transcription 3. Furthermore, amlexanox decreased the activation and inflammatory responses in Kupffer cells. Collectively, we found that inhibition of the TBK1 and IKKε by amlexanox is a promising therapeutic strategy to cure liver fibrosis.

TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration

“…These data suggested that TBK1 antagonist may modulate the immunosuppressive microenvironment by inhibiting the secretion of inflammatory cytokines in HCC cells and cancer-associated fibroblasts. Furthermore, consistent with the other study ( 61 ), our results showed the suppression of the activation of hepatic stellate cells and liver fibrosis by TBK1 antagonist ( Supplementary Figure 5C ). Due to the promoting effect of hepatic fibroinflammatory condition on the tumor immunosuppression ( 5 ), it is possible that the TBK1 antagonist attenuated the HCC immunosuppression by reducing the fibrosis and inflammatory environment of liver.…”

Isoproterenol-Induced Cardiomyopathy Recovery Intervention: Amlexanox and Forskolin Enhances the Resolution of Catecholamine Stress-Induced Maladaptive Myocardial Remodeling

“…Individually, AMLX and FSKN treatments promoted myocardial fibrosis resolution effectively compared to the placebo (in ICM+ PbT) ( Figures 3E–G ). Zhou et al had previously shown the anti-fibrotic potencies of AMLX treatment ( 28 ). Similarly, consistent with our findings, FSKN treatments were shown by El-Agroudy et al and Roberts et al to exert anti-fibrotic effects by inhibiting fibroblast activation, proliferation, and differentiation ( 29 , 30 ).…”

Role of IKKε in the Metabolic Diseases: Physiology, Pathophysiology, and Pharmacology

“…In terms of liver fibrosis, mice were treated with a 0.1% diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for four consecutive weeks to establish a liver fibrosis model. The results showed that phosphorylated IKKε/TBK1 was increased in HSCs ( Zhou et al, 2020b ). After treatment with AM, mice with hepatobiliary fibrosis showed significantly improved liver function, lower serum AST, and ALT levels and reduced inflammation of liver Kupffer cells (KCs) ( Zhou et al, 2020b ).…”

“…The results showed that phosphorylated IKKε/TBK1 was increased in HSCs ( Zhou et al, 2020b ). After treatment with AM, mice with hepatobiliary fibrosis showed significantly improved liver function, lower serum AST, and ALT levels and reduced inflammation of liver Kupffer cells (KCs) ( Zhou et al, 2020b ). During this process, AM inhibited the phosphorylation of IKKε/TBK1 in hepatic Kupffer cells, which may affect the phosphorylation of downstream STAT3.…”

“…During this process, AM inhibited the phosphorylation of IKKε/TBK1 in hepatic Kupffer cells, which may affect the phosphorylation of downstream STAT3. STAT3 phosphorylation and α-SMA expression were decreased when AM was co-incubated with HSCs and TGF-β–activated LX-2 cell lines (hepatic stellate cell) ( Zhou et al, 2020b ). STAT3 was specifically found in fibroblasts and HSCs, and not in hepatocytes.…”