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

Area of Science:

• Pharmacology
• Molecular Biology
• Pulmonary Medicine

Background:

• Pulmonary fibrosis (PF) is a progressive lung disease with limited treatment options.
• Identifying novel anti-fibrotic drugs and therapeutic targets is crucial for managing PF.
• Celastrol, derived from Tripterygium wilfordii, exhibits anti-fibrotic properties, but its mechanisms are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms and direct targets of celastrol in combating pulmonary fibrosis.
• To investigate celastrol's potential as a therapeutic agent for PF.

Main Methods:

• Network pharmacology analysis was employed to identify potential targets.
• Biotin-affinity pulldown assays, molecular docking, and molecular dynamics simulations were used to confirm direct targeting.
• Mechanistic studies involved assessing the effects of celastrol on PCAF, NF-κB acetylation, and TGF-β induced epithelial-to-mesenchymal transition (EMT).
• In vitro and in vivo models, including a bleomycin-induced mouse model of PF, were utilized.

Main Results:

• Celastrol was identified as a direct inhibitor of P300/CBP-associating factor (PCAF), a histone acetyltransferase.
• Celastrol suppressed PCAF-mediated acetylation of NF-κB.
• Celastrol effectively inhibited TGF-β induced epithelial-to-mesenchymal transition (EMT) in vitro, reducing cell migration and invasion.
• Celastrol demonstrated protective effects against bleomycin-induced pulmonary fibrosis in a mouse model.

Conclusions:

• PCAF is a novel therapeutic target for pulmonary fibrosis.
• Celastrol represents a promising therapeutic candidate for PF, acting through the PCAF/NF-κB pathway to inhibit EMT.