Luteolin as a potential intervention for bleomycin-induced pulmonary fibrosis: targeting the AKT/mTOR/HIF-1α/MMP2 axis.

Pulmonary fibrosis (PF) is a life-threatening interstitial lung disease that endangers human health. Luteolin (LUT), a naturally occurring flavonoid, has exhibited potential effects against pulmonary fibrosis. However, its mechanism of action remains unclear. Here, we investigated the therapeutic effects of LUT against PF and explored its underlying molecular mechanisms. Bioinformatics analysis was used to predict LUT targets. PF was induced in mice via a single intratracheal instillation of bleomycin (BLM). The effects of LUT were evaluated using histopathology, Western blotting, real-time quantitative polymerase chain reaction, and immunofluorescence. HIF-1α siRNA interference was used for mechanistic validation. The experimental findings revealed that bioinformatics prediction highlighted the HIF-1 signaling pathway. LUT significantly alleviated BLM-induced lung injury and suppressed epithelial-mesenchymal transition and extracellular matrix deposition. Mechanistically, LUT downregulated the expression of AKT, mTOR, HIF-1α, and MMP2. The siRNA knockdown of HIF-1α confirmed its central role. This study demonstrates that LUT ameliorates PF by modulating the AKT/mTOR/HIF-1α/MMP2 axis, providing novel evidence for the structural verification of this specific signaling cascade and supporting its potential as an agent for lung health.