Integrated Transcriptomic and Single-Cell Analyses Link ATP7A, a Cuproptosis-Related Hub Gene, to ECM-Adhesion Signaling Dysfunction in UVB-Induced Skin Photodamage

<h4>Objective</h4>To investigate the link between UVB-induced skin photodamage and cuproptosis, and identify key regulatory genes.<h4>Methods</h4>Transcriptomic data from UVB-irradiated human skin (GSE41078) were obtained from GEO. Differentially expressed genes (DEGs) were identified, followed by GO and KEGG enrichment, and WGCNA. Key regulators were defined by intersecting DEGs, cuproptosis-related genes (CRGs), and the WGCNA module most correlated with photodamage. Single-cell RNA-seq data (GSE289389) were used to assess ATP7A expression in keratinocytes and to infer cell-cell communication (CellChat), focusing on ECM and adhesion signaling. Hub genes were validated via qRT-PCR and Western blot in UVB-induced acute photodamage cells and mouse models.<h4>Results</h4>Examination of the GSE41078 dataset revealed 509 DEGs associated with photodamage. WGCNA identified the blue module as most strongly correlated with photodamage. Cross-referencing 978 core module genes with 55 CRGs and 509 DEGs identified a single hub gene, ATPase copper transporting alpha (ATP7A). Single-cell analysis confirmed significant ATP7A downregulation after UVB exposure (p = 1.83 × 10^-5) and showed that ATP7A-high keratinocytes exhibited stronger integration with stromal cells via enhanced ECM-adhesion signaling (e.g. collagen, laminin), whereas ATP7A-low cells displayed weakened responsiveness to microenvironmental cues. Experimental confirmation suggested that both mRNA and protein expression of ATP7A were markedly diminished in photodamaged cellular and mouse models (P < 0.05), aligning with the computational predictions.<h4>Conclusion</h4>This study suggests a potential association between ATP7A downregulation and UVB-induced photodamage with possible relevance to cuproptosis-related pathways. ATP7A downregulation is associated with reduced ECM-adhesion signaling interactions in keratinocytes, as indicated by CellChat. This analysis provides new clues to the mechanism of photodamage and suggests that ATP7A may be involved in the functional regulation of skin photodamage.