Targeting Circadian Rhythm Disruption in Glaucoma: PTGDS Mediates Trabecular Meshwork Fibrosis and Is Therapeutically Targeted by Aprepitant.

Purpose: Trabecular meshwork (TM) fibrosis, which causes ocular hypertension (OHT), remains a key therapeutic challenge in glaucoma. Given the emerging link between circadian rhythm disruption and glaucoma, we sought to identify novel fibrotic mediators related to circadian genes, and screen for potential inhibitors to assess their therapeutic effect. Methods: We performed an integrated analysis of human TM transcriptome data to identify key circadian rhythm-related differentially expressed genes (CRRDEGs). We confirmed the hub gene's upregulation in an OHT mouse model. We then performed virtual screening and molecular docking to identify a potential inhibitor from existing drugs, which was subsequently tested in vitro for anti-fibrotic efficacy. Results: PTGDS emerged as the hub gene among 15 CRRDEGs, showing significant overexpression in the TM of OHT mice. Virtual screening indicated that aprepitant as the top candidate inhibitor, showing the lowest binding affinity for PTGDS. Subsequent in vitro tests confirmed that aprepitant partially rescued human TM cell viability from TGFβ-induced fibrotic stress. It also effectively downregulated the expression of both PTGDS and established fibrosis markers. Conclusions: PTGDS, a key circadian-related gene, is a novel mediator of TM fibrosis. Our findings demonstrate that targeting PTGDS with aprepitant can ameliorate the fibrotic phenotype in vitro. This validates PTGDS as a promising, druggable target for glaucoma therapy. Translational Relevance: This study identifies the PTGDS-mediated fibrotic pathway as a druggable target in glaucoma. Our findings provide a preclinical rationale for evaluating the US Food and Drug Administration (FDA)-approved drug aprepitant as a repurposed therapeutic, offering a new strategy for the development of anti-fibrotic treatments.