Targeting insulin-like growth factor 1 signaling with Linsitinib to modulate fibroblast plasticity and attenuate pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal, irreversible lung disorder with limited treatment options. Pathogenic drivers include fibroblast-to-myofibroblast transition, excessive collagen deposition, and inflammatory infiltration. Elevated circulating insulin-like growth factor-1 (IGF-1) levels and dysregulated activation of the IGF-1 receptor (IGF-1R) are implicated in multiple pathological conditions such as cancer, chronic inflammation, and fibrotic diseases. Linsitinib, a small-molecule tyrosine kinase inhibitor, selectively targets IGF-1R activation. However, its therapeutic potential and pharmacological mechanisms in IPF remain unexplored. In this study, we aimed to evaluate the efficacy and molecular basis of Linsitinib for IPF treatment. High-throughput sequencing revealed IGF-1 upregulation in the lung tissues of a murine IPF model. In vivo, oral Linsitinib attenuated fibrosis and inflammation in bleomycin-induced pulmonary fibrosis, inhibiting IGF-1R phosphorylation. In vitro, Linsitinib suppressed transforming growth factor β1-induced fibroblast-to-myofibroblast transition (marked by reduced alpha smooth muscle actin and fibronectin) and collagen biosynthesis (COL1A1, COL3A1) in primary lung fibroblasts. Transcriptomic profiling and lentiviral-based functional assays demonstrated that Linsitinib upregulated peroxisome proliferator-activated receptor gamma (PPARγ) expression by blocking IGF-1R phosphorylation, thereby promoting adipogenic transdifferentiation. Ex vivo, human IPF lung explants confirmed Linsitinib mitigated fibrosis and collagen accumulation via the IGF-1/IGF-1R/PPARγ axis. These findings suggest that Linsitinib exerts its effects against fibrosis by targeting IGF-1R-driven signaling pathways, making it a potential therapeutic agent for IPF.