Celastrol Activates SIRT1/PGC-1α/Nrf2 Axis to Inhibit Oxidative Damage for Subconjunctival Fibrosis Alleviation.

Area of Science:

• Ophthalmology
• Cell Biology
• Pharmacology

Background:

• Subconjunctival fibrosis, leading to symblepharon and recurrent pterygium, poses a significant threat to vision.
• Previous research identified celastrol as a potential inhibitor of subconjunctival fibrosis.

Purpose of the Study:

• To investigate the mechanisms by which celastrol-nanomicelles (Cel) inhibit subconjunctival fibrosis.
• To explore the role of the SIRT1/PGC-1α/Nrf2 axis in Cel's antifibrotic effects.

Main Methods:

• Established rat subconjunctival injury and human pterygium fibroblast models.
• Utilized RNA-seq, immunofluorescence, and Western blot to analyze Cel's targets and pathways.
• Confirmed the involvement of the SIRT1/PGC-1α/Nrf2 axis using a selective SIRT1 antagonist (EX527).

Main Results:

• Cel effectively attenuated oxidative damage and subconjunctival fibrosis in vivo and in vitro.
• RNA-seq identified SIRT1 signaling and oxidative stress regulation as key targets of Cel.
• Cel inhibited fibrosis by activating the SIRT1/PGC-1α/Nrf2 axis and suppressing the TGF-β1/Smad2/3 pathway.

Conclusions:

• Cel alleviates subconjunctival fibrosis by inhibiting oxidative damage through activation of the SIRT1/PGC-1α/Nrf2 signaling pathway.
• This study provides a novel mechanism for celastrol as a potential therapeutic agent for subconjunctival fibrosis.