Targeting CRBN With Thalidomide Suppresses Fibrosis After Glaucoma Drainage Surgery Through NF-κB Pathway Inhibition

Fibrosis after glaucoma drainage surgery (GDS) is the main factor behind glaucoma surgery failures. Previous studies showed that cereblon (CRBN) protein is involved in tissue differentiation, although its role in glaucoma remains unknown. Herein we explored the role of CRBN and its ligand thalidomide (THD) in fibrosis after GDS.

Using a rat GDS model and TGF-β2-induced cell model, we investigated the functions of CRBN and THD. CRBN expression in Tenon capsule tissue was detected using immunofluorescence. Filtering bleb survival was monitored after surgery. Protein levels of α‑smooth muscle actin (SMA), fibronectin (FN), and proliferating cell nuclear antigen (PCNA) were measured by Western blotting and immunohistochemistry. Activation of the nuclear factor (NF)‑κB pathway was evaluated via detecting P65 and p‑P65 levels.

CRBN expression was upregulated in Tenon capsule tissue after GDS. THD treatment significantly attenuated CRBN expression. Moreover, THD dose-dependently inhibited TGF-β2-induced cell proliferation. Western blotting confirmed that THD suppresses TGF-β2-induced transdifferentiation and proliferation of human Tenon fibroblasts. In vivo, topical THD application prolonged filtering bleb survival and restrained α-SMA expression. Mechanistically, THD inhibited P65 phosphorylation, thereby preventing the activation of the NF-κB pathway.

CRBN is a key protein regulating fibrosis following GDS. THD exerts anti-fibrotic effects by targeting CRBN and inhibiting the NF-κB pathway. These findings unveil a novel intervention target, CRBN, for attenuating fibrogenesis after GDS.