Abstract

Environmental stress does not uniformly disrupt biological systems but instead induces selective reorganization of regulatory networks. What extracellular matrix dynamics and intracellular redox systems are co-ordinately rewired under stress remains poorly defined. Here, we apply a UVA-regulated hub-centred network analysis to resolve UVA-induced coupling between hyaluronic acid (HA)–associated extracellular signalling and ascorbic acid (AA)–associated intracellular redox networks in human skin. Integration of curated HA and AA interactomes with UVA-responsive transcriptomic data (GEO accession GSE240226; UVA-irradiated versus untreated primary human dermal fibroblasts, n = 3 per group) shows that differentially expressed genes (DEGs) occupy positions of significantly higher topological centrality than non-responsive nodes in the HA interactome and in the integrated HA–AA network (Mann–Whitney U test and 10,000-fold label-permutation testing, p < 0.01 for degree, betweenness, closeness, stress and radiality), whereas no such enrichment was detected in the AA interactome (p > 0.05). This asymmetry is dominated by HA-centred inflammatory and matrix-regulatory nodes and modulated by AA-associated redox and transport proteins. Structure-based docking predicts oligomer length–dependent differences in HA receptor compatibility: CD44 returned favourable docking scores for the shorter oligomers HA4 and HA6 but unfavourable scores for HA8, whereas LYVE1 retained favourable scores across all three oligomer lengths tested. These are predictions of structural compatibility and are not measurements of binding affinity or receptor selectivity. In parallel, the cytosolic redox effectors CLIC1 and GSTO1 — selected on functional and biochemical grounds rather than on network centrality, and which were neither consensus hubs nor DEGs in this analysis — returned favourable predicted docking with dehydroascorbate, as did the UVA-downregulated transporters SLC2A3 and SLC2A14. Together, these findings propose a systems-level framework linking extracellular matrix signalling and intracellular redox regulation during UVA stress. This is an entirely in silico, hypothesis-generating study: it prioritises candidate molecules linking HA- and AAassociated pathways for subsequent experimental testing, but the candidates reported here are computational predictions and are not proposed as validated biomarkers or therapeutic targets.

Keywords

UVA stress, hyaluronic acid signalling, ascorbic acid redox metabolism, hubcentred network analysis, extracellular–intracellular coupling