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Pulmonary fibrosis is a severe condition with limited therapeutic options and characterized by increased fibroblast activation and progressive accumulation of extracellular matrix. Ghrelin, a gastrointestinal hormone, has been reported to possess protective roles in lung diseases including pulmonary fibrosis. However, the precise mechanisms underlying the protective effects of ghrelin remain unknown. The present study was designed to investigate the effects of ghrelin on transforming growth factor-β1 (TGF-β1)-induced pulmonary fibrosis in vitro and in vivo and the possible mechanism of action. It was found that ghrelin significantly attenuated TGF-β1-induced fibrotic responses in human lung fibroblast (IMR-90) cells and bleomycin (BLM)-induced fibrotic lung tissues. Meanwhile, ghrelin decreased the expressions of miR-125a-5p and phosphorylated smad2/3 and increased protein expressions of Kruppel-like factor 13 (KLF13) in vivo and in vitro. Ghrelin–induced anti-fibrotic effects and smad2/3 downregulation in TGF-β1-stimulated IMR-90 cells were markedly reversed by miR-125a-5p mimics and KLF13 siRNA. Furthermore, miR-125a-5p directly targeted KLF13 in IMR-90 cells. Our findings suggest that ghrelin attenuates TGF-β1-induced pulmonary fibrosis via the miR-125a-5p/KLF13 axis, which supports ghrelin as a new therapeutic agent against pulmonary fibrosis by antagonizing the TGF-β1 signaling pathway. [Display omitted] • Ghrelin attenuates TGF-β1-induced pulmonary fibrosis via the miR-125a-5p/KLF13 axis. • Targeting the miR-125a-5p/KLF13 axis reversed ghrelin-induced smad2/3 downregulation. • TGF-β1 regulated the miR-125a-5p/KLF13 axis in a smad-independent non-canonical manner. [ABSTRACT FROM AUTHOR]