Macrophage differentiation is closely associated with idiopathic pulmonary fibrosis (IPF) initiation. Herein, we show that EZY-1, a novel peptide derived from Eucheuma, regulates macrophage differentiation to inhibit IPF. Macrophage differentiation was detected by analyzing the surface antigens of the macrophages using flow cytometry. The effect of EZY-1 on cell proliferation was assessed. Signaling molecules involved in macrophage differentiation and fibrosis were detected by Western blot and enzyme-linked immunosorbent assays. The results showed that EZY-1 suppressed BLM-induced pulmonary fibrosis, with a decrease in type M2 macrophages. Simultaneously, EZY-1 reduced the amount of TGF-β1 secreted by M2 macrophages. In addition, EZY-1 downregulated COL1A1, TGF-β, and p-Smad3 and upregulated p-β-catenin in fibroblasts induced by M2 macrophages. Our results confirmed that EZY-1 inhibits IPF by inhibiting type M2 macrophage differentiation, which may be associated with the expression of Rictor and SHP2. Thus, EZY-1 can potentially be used as a drug for treating IPF....

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