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Unveiling Disulfidptosis and Cuproptosis Vulnerabilities in Pterygium: A Transcriptomic Analysis and In-Silico Drug
1Department of Ophthalmology, Servergazi Hospital, Bereketler, Bereket Cd. No:1, Merkezefendi 20000, Turkey.
Objectives:
Pterygium is an invasive, hyperproliferative fibrovascular disorder of the ocular surface characterized by frequent postoperative recurrence and resistance to apoptosis. This study investigated transcriptional alterations in genes related to the regulated cell death pathways disulfidptosis and cuproptosis in pterygium and explored potential pharmacological candidates through in-silico drug repurposing.
Methods:
High-throughput RNA-sequencing data (GEO accession GSE155776) from primary pterygium tissues (n = 8) and healthy conjunctival controls (n = 8) were analyzed. The expression profiles of 15 disulfidptosis-related and 13 cuproptosis-related genes were evaluated. Differential expression signatures were subsequently analyzed using the L1000CDS2 platform in reverse mode to identify perturbagens with transcriptional effects opposing the pterygium-associated signature.
Results:
Transcriptomic analysis demonstrated marked alterations in actin-cytoskeletal genes, with profound downregulation of ACTB and WASF2 and upregulation of DSTN and CAPZA1, suggesting a potential vulnerability to disulfide stress. Cuproptosis-related analysis showed increased expression of mitochondrial metabolic genes, including PDHB and DLD, together with significant overexpression of the copper transporter SLC31A1, consistent with transcriptional remodeling of mitochondrial metabolic and copper-handling programs. In-silico drug repurposing identified several FDA-approved drugs with anti-correlative perturbational profiles, including Auranofin, Ouabain, Digitoxin, and Neratinib.
Conclusions:
Pterygium is associated with coordinated transcriptional alterations involving disulfidptosis- and cuproptosis-related gene networks, suggesting potential structural and metabolic vulnerabilities. In-silico drug repurposing identified several pharmacological candidates whose transcriptional effects oppose the observed disease-associated signature. These findings provide a rationale for further experimental investigation of these pathways and candidate compounds in pterygium.