Background: Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults. Ferroptosis, an iron-dependent form of programmed cell death, contributes to DR pathogenesis. Baicalein, a natural flavonoid, exhibits antioxidant and anti-inflammatory effects and is a potential ferroptosis inhibitor. Methods: We applied a network pharmacology approach to explore Baicalein's therapeutic potential in DR. Differentially expressed genes (DEGs) were identified from GSE102485, and ferroptosis-related genes (FRGs) were obtained from FerrDb. Baicalein-related targets were retrieved from TCMSP and PharmMapper. Protein-protein interaction (PPI) networks were constructed using STRING and Cytoscape. GO and KEGG pathway enrichment analyses were performed. Single-cell RNA sequencing (scRNA-seq) data from GSE178121 were analyzed to determine core target expression across retinal cell types. Molecular docking and molecular dynamics simulations assessed Baicalein's binding affinity and stability with key targets. Results: A total of 4,279 DEGs and 120 ferroptosis-related DEGs were identified, with 21 overlapping targets among DR, ferroptosis, and Baicalein; eleven core targets were selected based on network topology. Enrichment analysis revealed involvement in critical DR-related pathways, including HIF-1A, TNF, PI3K-Akt, and MAPK signaling. scRNA-seq highlighted broad HIF1A expression across retinal cells, particularly in bipolar cells and rods. Molecular docking showed favorable binding with PPARG and ALB, and dynamics simulations indicated stable interactions, suggesting Baicalein can effectively modulate ferroptosis pathways. Conclusions: Integrating network pharmacology and single-cell transcriptomics, this study identifies Baicalein as a promising candidate for DR therapy by targeting ferroptosis. These findings support further preclinical and clinical investigation to protect diverse retinal cell populations from ferroptotic damage.
Liu et al. (Wed,) studied this question.