Impaired macroautophagy/autophagy is involved in the pathogenesis of hepatic fibrosis. However, how aberrant autophagy promotes fibrosis is far from understood. Here, we aimed to define a previously unrevealed pro-fibrotic mechanism for the stress protein TRIB3 (tribbles pseudokinase 3)-mediated autophagy dysfunction. Human fibrotic liver tissues were obtained from patients with cirrhosis who underwent an open surgical repair process. The functional implications of TRIB3 were evaluated in mouse models of hepatic fibrosis induced by bile duct ligation (BDL) or thioacetamide (TAA) injection. Human fibrotic liver tissues expressed higher levels of TRIB3 and selective autophagic receptor SQSTM1/ p62 (sequestosome 1) than nonfibrotic tissues and the elevated expression of TRIB3 and SQSTM1 was positively correlated in the fibrotic tissues. Silencing Trib3 protected against experimentally induced hepatic fibrosis, accompanied by restored autophagy activity in fibrotic liver tissues. Furthermore, TRIB3 interacted with SQSTM1 and hindered its binding to MAP1LC3/LC3, which caused the accumulation of SQSTM1 aggregates and obstructed autophagic flux. The TRIB3-mediated autophagy impairment not only suppressed autophagic degradation of late endosomes but also promoted hepatocellular secretion of INHBA/Activin A-enriched exosomes which caused migration, proliferation and activation of hepatic stellate cells (HSCs), the effector cells of liver fibrosis. Disrupting the TRIB3-SQSTM1 interaction with a specific helical peptide exerted potent protective effects against hepatic fibrosis by restoring autophagic flux in hepatocytes and HSCs. Together, stress-elevated TRIB3 expression promotes hepatic fibrosis by interacting with SQSTM1 and interfering with its functions in liver-parenchymal cells and activating HSCs. Targeting this interaction is a promising strategy for treating fibroproliferative liver diseases.
BackgroundHeart failure (HF) is one of the most significant causes of morbidity and mortality for the cardiovascular risk population. We found previously that extracellular HSP70 (heat shock protein) is an important trigger in cardiac hypertrophy and fibrosis, which are associated with the development of heart dysfunction. However, the potential role of HSP70 in response to HF and whether it could be a target for the therapy of HF remain unknown.Methods and ResultsAn HF mouse model was generated by a single IP injection of doxorubicin at a dose of 15 mg/kg. Ten days later, these mice were treated with an HSP70 neutralizing antibody for 5 times. We observed that doxorubicin treatment increased circulating HSP70 and expression of HSP70 in myocardium and promoted its extracellular release in the heart. Blocking extracellular HSP70 activity by its antibody significantly ameliorated doxorubicin‐induced left ventricular dilation and dysfunction, which was accompanied by a significant inhibition of cardiac fibrosis. The cardioprotective effect of the anti‐HSP70 antibody was largely attributed to its ability to promote the resolution of myocardial inflammation, as evidenced by its suppression of the toll‐like receptor 2–associated signaling cascade and modulation of the intracellular distribution of the p50 and p65 subunits of nuclear factor‐κB.ConclusionsExtracellular HSP70 serves as a noninfectious inflammatory factor in the development of HF, and blocking extracellular HSP70 activity may provide potential therapeutic benefits for the treatment of HF.
Liver fibrosis, a major cause of morbidity and mortality worldwide, leads to liver damage, seriously threatening human health. In our previous study, we demonstrated that 14-kDa phosphohistidine phosphatase (PHP14) was upregulated in fibrotic liver tissue and involved in the migration and lamellipodia formation of hepatic stellate cells (HSCs). In this study, we evaluated PHP14 as a therapeutic target for liver fibrosis and investigated the mechanism by which it mediates liver fibrosis. AAV-shPhpt1 administration significantly attenuates CCl4-induced liver fibrosis in mice. In particular, fibrosis-associated inflammatory infiltration was significantly suppressed after PHP14 knockdown. Mechanistically, PHP14 regulated macrophage recruitment, infiltration and migration by affecting podosome formation of macrophages. Inhibition of PHP14 decreased the expression of the fibrogenic signature at the early stage of liver fibrogenesis and the activation of HSCs in vivo. Thus, PHP14 can be considered a potential therapeutic target for liver fibrosis.
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