Curcumin protects retinal photoreceptors in Glaucoma by activating prostaglandin D2 synthase-dependent NRF2 signaling

Glaucoma, a leading cause of irreversible blindness, involves oxidative stress-mediated damage to retinal photoreceptors. This study elucidates the molecular mechanism by which curcumin, a natural compound, protects retinal cells in glaucoma. Molecular docking and biochemical assays revealed that curcumin binds prostaglandin D2 synthase (PTGDS) with high affinity, leading to marked upregulation of PTGDS expression. In vitro experiments using H₂O₂-treated 661 W retinal cells showed that PTGDS overexpression suppressed reactive oxygen species (ROS) accumulation, inflammation, and apoptosis while enhancing proliferation. Transcriptomic profiling showed that PTGDS knockdown disrupted nuclear factor erythroid 2-related factor 2 (NRF2) signaling and downregulated key antioxidant genes. Mechanistically, curcumin-induced PTGDS expression activated NRF2, increased phosphorylation of AMP-activated protein kinase (AMPK) and ERK, upregulated Bcl-2, and inhibited Bax and caspase-3 cleavage. These effects were abolished by PTGDS knockdown. In vivo validation using a paraquat-induced glaucoma mouse model confirmed that curcumin improved visual function (via pattern electroretinography, optokinetic response, and visual evoked potentials), reduced retinal oxidative stress markers (malondialdehyde, superoxide dismutase, glutathione), and attenuated inflammatory cytokines (Interleukin [IL]-1β, Tumor Necrosis Factor Alpha [TNF-α]). PTGDS knockdown negated these therapeutic benefits. Together, these findings establish PTGDS as a critical mediator of curcumin-induced NRF2 activation, highlighting a novel cross-species neuroprotective pathway and a promising therapeutic target for glaucoma.