Usnic Acid

Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease with limited therapeutic options. The pathogenesis of IPF has been reported to be closely associated with the aberrant activation of the Wnt/β-catenin signaling pathway. Zinc finger protein 70 (ZNF70), a member of the zinc finger protein family, serves as a significant target for the treatment of inflammation-related diseases. Usnic acid (UA), a dibenzofuran compound extracted from Usnea found in Changbai Mountain, has demonstrated potent anticancer and anti-inflammatory properties. However, its mechanism of action in pulmonary fibrosis remains unexplored. In this study, we report for the first time that UA-mediated inhibition of ZNF70 as a key regulatory mechanism, which prevents the expression of fibrosis markers, including α-smooth muscle actin (α-SMA) and collagen. Furthermore, UA inhibits the ZNF70-mediated nuclear translocation of β-catenin, thereby preventing the activation of the Wnt/β-catenin signaling pathway and suppressing the epithelial-mesenchymal transition (EMT) process. Additionally, we observed that ZNF70 promotes the activation of mouse lung fibroblasts, a process that can be reversed by UA treatment. In vivo, we established a mouse model of pulmonary fibrosis through AAV-mediated ZNF70 knockdown and intratracheal instillation of bleomycin (BLM). We found that UA can ameliorate BLM-induced pulmonary fibrosis by inhibiting ZNF70. In summary, we have demonstrated for the first time that UA acts as an inhibitor of ZNF70, preventing fibroblast activation and effectively hindering the onset and progression of pulmonary fibrosis. Our research provides a novel concept and theoretical framework for developing an innovative treatment strategy targeting ZNF70, with UA as the lead compound.

Usnic acid, a compound from Usneae Filum, has shown notable antitumor effects. Nevertheless, the mechanism of its anti‐NSCLC action remains incompletely elucidated. This study used metabolomics, network pharmacology, molecular docking, and dynamics simulation to investigate usnic acid's potential mechanism on NSCLC utilizing A549 cell samples. The integration of metabolomics and network pharmacology was confirmed through molecular docking and molecular dynamics simulation. Combining data‐dependent acquisition (DDA) and data‐independent acquisition (DIA) enables maximal MS/MS coverage of endogenous substances in complex biological matrices. Metabolomics based on DDA and DIA revealed 47 potential metabolites linked to usnic acid's therapeutic effects on NSCLC. Network pharmacology identified 24 targets, with key pathways including cancer, human cytomegalovirus infection, and p53 signaling. A network analysis highlighted myeloperoxidase (MPO) as a shared target, with molecular docking and dynamics simulations confirming strong binding and stability between usnic acid and MPO. This study uncovered usnic acid's molecular mechanisms in NSCLC, primarily through MPO targeting and modulation of purine metabolism. MPO inhibition attenuates oxidative stress‐driven purine catabolism, reduces uric acid‐induced inflammation, and restores metabolic homeostasis. These findings illuminate novel mechanisms of usnic acid's anticancer potential and advance mechanistic insights into traditional Chinese medicine (TCM) for clinical oncology applications.