摘要：SummaryPersistent activation of fibroblasts and resistance of myofibroblasts to turnover play important roles in organ-tissue fibrosis development and progression. The mechanism that mediates apoptosis resistance of myofibroblasts is not understood. Here, we report that myofibroblasts express and secrete PKM2. Extracellular PKM2 (EcPKM2) facilitates progression of fibrosis by protecting myofibroblasts from apoptosis. EcPKM2 upregulates arginase-1 expression in myofibroblasts and therefore facilitates proline biosynthesis and subsequent collagen production. EcPKM2 interacts with integrin αvβ3on myofibroblasts to activate FAK-PI3K signaling axis. Activation of FAK-PI3K by EcPKM2 activates downstream NF-κB survival pathway to prevent myofibroblasts from apoptosis. On the other hand, activation of FAK- PI3K by EcPKM2 suppresses PTEN to subsequently upregulate arginase-1 in myofibroblasts. Our studies uncover an important mechanism for organ fibrosis progression. More importantly, an antibody disrupting the interaction between PKM2 and integrin αvβ3is effective in reversing fibrosis, suggesting a possible therapeutic strategy and target for treatment of organ fibrosis.Graphical abstractDisplay OmittedHighlights•Extracellular PKM2 (EcPKM2) facilitates organ fibrosis progression•EcPKM2 promotes apoptosis resistance and collagen production in myofibroblasts•EcPKM2 activates αvβ3-FAK-PI3K signaling axis•An antibody disrupting PKM2 and αvβ3interaction reverses lung and liver fibrosisBiological sciences; Molecular biology; Cell biology
