Targeting the PPAR-γ/OPTN axis to inhibit apoptosis in steroid-induced glaucoma.

Steroid-induced glaucoma (SIG) is the most common form of secondary glaucoma and is characterized by trabecular meshwork dysfunction and elevated intraocular pressure. Here, we investigated the contribution of trabecular meshwork cell (TMC) apoptosis to SIG pathogenesis using both in vivo and in vitro models. In a rat SIG model, reduced TMC density and increased apoptosis were observed. Integrated transcriptomic and proteomic analyses identified reduced peroxisome proliferator-activated receptor-γ (PPAR-γ) expression in SIG TMCs, which was validated by immunohistochemistry and immunoblotting. Functional enhancement of PPAR-γ attenuated TMC apoptosis and suppressed the activation of the NF-κB/Bax/Bcl-2/caspase-3 signaling pathway. Mechanistically, optineurin (OPTN) was identified as a downstream target of PPAR-γ, with PPAR-γ directly binding to the OPTN promoter to regulate its transcription. Genetic disruption of OPTN diminished the protective effects of PPAR-γ. In vivo modulation of the PPAR-γ/OPTN axis alleviated trabecular meshwork injury, reduced apoptosis, and lowered intraocular pressure, highlighting a regulatory pathway linked to SIG progression.