Purpose: Retinal degeneration is the primary cause of blindness and is characterized by progressive dysfunction and death of retinal cells, leading to irreversible vision impairment. As far as is known, there are currently no effective treatments for this condition. The identification of novel therapeutic targets remains a critical challenge. Methods: To address this vital issue, we performed an in-depth transcriptome analysis of the sodium iodate-induced cell model (NaIO3-treated cells), further identified the differential gene expression and common pathways, performed enrichment analysis, constructed protein-protein interaction (PPI) networks, and screened for three core DNA replication-related genes (MCM4, MCM5, and MCM7). Subsequently, quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry assays were performed to verify the expression levels of hub genes in the NaIO3-treated adult retinal pigment epithelial cell line-19 and animal models. Results: The pathways were mainly focused on DNA replication in the enrichment analysis. PPI network analysis revealed that minichromosome maintenance complex genes associated with DNA replication were core genes for retinal degeneration. qPCR and immunohistochemistry assays showed that the expression levels of hub genes were downregulated in the NaIO3-treated cell and animal models. Conclusions: Collectively, our bioinformatics analysis, coupled with experimental validation, identified three core DNA replication-related genes (MCM4, MCM5, and MCM7) with potential implications in retinal degeneration, suggesting their roles in the disease process. These findings shed light on the molecular underpinnings of retinal degeneration and pave the way for the development of targeted therapies aimed at modulating DNA replication-related gene activity to treat retinal degeneration.