Ganoderma microsporum immunomodulatory protein (GMI) ameliorates pulmonary fibrosis by regulating the PI3K/Akt/mTOR signaling

<bold>Background:</bold> Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease of unknown cause that affects 3 million people worldwide and has limited therapeutic options. It is characterized by aberrant myofibroblast activation and excessive extracellular matrix deposition in the lungs. Age, pollutants, and infectious agents are known risk factors for IPF development and progression. <bold>Aims:</bold> <italic>Ganoderma microsporum</italic> immunomodulatory protein (GMI) is a fungal protein derived from <italic>Ganoderma microsporum</italic> and has shown anti-cancer activity by inhibiting epithelial-to-mesenchymal transition (EMT) and promoting autophagy and apoptosis. This study aimed to evaluate the therapeutic potential of GMI for pulmonary fibrosis (PF). <bold>Methods:</bold> A murine model of bleomycin (BLM)-induced PF was used to assess the antifibrotic effects of GMI in the lungs. LL29 human lung fibroblasts (HLF) were used to investigate the effect of GMI on TGF-β1-induced myofibroblast activation. <bold>Results:</bold> GMI improved the overall survival and body weight loss of BLM-induced mice. In particular, GMI mitigated lung inflammation. Besides, GMI promoted lung structural integrity and diminished fibrotic markers. On the other hand, GMI reduced cell migratory behavior. Mechanistic studies revealed that GMI modulated PI3K/Akt/mTOR signaling and promoted autophagy in LL29 HLF. <bold>Conclusion:</bold> GMI mitigated BLM-induced PF and inhibited TGF-β1-induced myofibroblast activation by mediating the PI3K/Akt/mTOR signaling pathway and autophagy. These findings highlight the therapeutic potential of GMI as a novel antifibrotic agent for the treatment of PF.