Celastrol Targets Cullin-Associated and Neddylation-Dissociated 1 to Prevent Fibroblast–Myofibroblast Transformation against Pulmonary Fibrosis

Celastrol
(CEL), a pentacyclic triterpene compound, has been proven
to have a definite antipulmonary fibrosis effect. However, its direct
targets for antipulmonary fibrosis remain unknown. In this study,
we designed and synthesized a series of celastrol-based probes to
identify the direct targets in human pulmonary fibroblasts using an
activity-based protein profiling strategy. Among many fished targets,
we identified a key protein, cullin-associated and neddylation-dissociated
1 (CAND1), which was involved in fibroblast–myofibroblast transformation
(FMT). More importantly, we found that the inhibitory effect of celastrol
on FMT is dependent on CAND1, through improving the interactions between
CAND1 and Cullin1 to promote the activity of Skp1/Cullin1/F-box ubiquitin
ligases. In silico studies and cysteine mutation experiments further
demonstrated that Cys264 of CAND1 is the site for conjugation of celastrol.
This reveals a new mechanism of celastrol against pulmonary fibrosis
and may provide a novel therapeutic option for antipulmonary fibrosis.