Revealing a new target: Celastrol alleviates pulmonary fibrosis by inhibiting PCAF

Pulmonary fibrosis (PF) is a serious interstitial lung disease characterized by declining pulmonary function but with few effective drugs and limited therapies. New anti-fibrosis drugs and targets are required to combat PF. Celastrol, a triterpenoids component isolated from Tripterygium wilfordii, has many kinds of pharmacological and physiological activities, such as anti-fibrosis, however its potential mechanisms and direct targets remain unclear. In this study, network pharmacology analysis, biotin-affinity pulldown assay, molecular docking and molecular dynamics simulation were used and found celastrol directly target P300/CBP-associating factor (PCAF), a Histone Acetyltransferase (HAT). Mechanistic investigation shown that celastrol inhibited the acetylation of NF-κB by suppressing PCAF. Strikingly, we found that celastrol suppressed TGF-β induced epithelial-to-mesenchymal transition (EMT) characterized by the decrease in migration and invasion in vitro and protect against bleomycin (BLM) induced mouse model of PF in vivo. Taken together, these findings indicate that PCAF is a new potential target for the treatment of PF and celastrol is a promising clinical candidate for the therapy of PF by target EMT mediated via PCAF/ NF-κB pathway.

Bleomycin; Celastrol; Epithelial-to-mesenchymal transition; PCAF; Pulmonary fibrosis.