Bioinformatics-Driven Target Discovery in Skin Photoaging and Preliminary Validation of the Natural Compound Acteoside

Objective To identify differentially expressed genes (DEGs), key pathways, and potential active compounds associated with skin photoaging using bioinformatics approaches, and to validate the interventional effects and molecular mechanisms of candidate compounds through cellular experiments, thereby highlighting the central role of bioinformatics in target and drug discovery. Methods Datasets GSE284483 and GSE296578 were obtained from the GEO database, merged, and adjusted for batch effects. The limma package was used to screen for DEGs. Functional annotations of DEGs were analyzed through GO, KEGG, and GSEA analyses. WGCNA identified core modules and key genes, while CIBERSORT assessed immune cell infiltration. A protein-protein interaction network was constructed using STRING, and potential active compounds were predicted via HERB2.0. Molecular docking was performed with AutoDock Vina. A UVB-induced photoaging model was established using human skin fibroblasts, with experimental groups including control, UVB model, and Acteoside treatment. Cell proliferation, apoptosis, ferroptosis, MMP expression, and collagen metabolism were evaluated using CCK-8, qPCR, colorimetric assays, and ELISA to validate bioinformatics predictions. Results A total of 765 DEGs were identified, enriched in biological processes such as cell motility, signal transduction, iron metabolism, and immune-related pathways. WGCNA identified ferroptosis-related genes (ATM, Cav1, Cdkn2a) and MMP family genes (MMP3, MMP9, MMP13) as key genes, with a significant positive correlation between MMP3 and ATM expression. Molecular docking revealed that Acteoside exhibited the highest binding affinity for ATM (binding free energy: -9.3 kcal/mol) and MMP3 (binding free energy: -7.9 kcal/mol). Cellular experiments confirmed that Acteoside reversed UVB-induced reductions in cell viability, corrected aberrant expression of apoptosis- and ferroptosis-related genes, suppressed MMP upregulation, and restored the balance between collagen synthesis and degradation, consistent with bioinformatics predictions. Conclusion This study demonstrates, through bioinformatics-driven analysis, that the ATM-MMP3 axis serves as a core regulatory pathway in skin photoaging. Acteoside exerts anti-photoaging effects by targeting this axis to inhibit apoptosis, ferroptosis, and extracellular matrix degradation. These findings provide new targets and candidate compounds for the prevention and treatment of skin photoaging, underscoring the efficacy of bioinformatics in guiding target and drug discovery.