From gut-derived metabolites to topical targets: 5-(3',4'-dihydroxyphenyl)-γ-valerolactone as an anti-inflammatory candidate for skin and mucosal inflammation.

Plant-derived compounds can be transformed by the human gut microbiota into postbiotic metabolites with distinct structures and biological activities, providing insight into the mechanisms underlying the pharmacological effects of medicinal plants. Among them, 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (DHPV), a microbial metabolite of procyanidins, has emerged as a promising bioactive molecule with therapeutic potential. This study evaluated the potential application of synthetically produced DHPV in inflammatory conditions, focusing on its effects on inflammatory responses and wound-healing processes in skin and mucosal cell models, including keratinocytes, dermal fibroblasts, and vaginal epithelial cells. Cell viability after DHPV treatment was assessed using the MTT assay. Anti-inflammatory activity was examined in TNF-α/IFN-γ-stimulated HaCaT keratinocytes, LTA-stimulated NHDF fibroblasts, and TNF-α-stimulated VK2 vaginal epithelial cells. The effect on wound healing was evaluated using a keratinocyte scratch assay, while LC-MS-based metabolomic profiling was performed in TNF-α/IFN-γ-stimulated HaCaT cells. DHPV significantly reduced the release of pro-inflammatory mediators in all tested models, including IL-6, IL-8, CCL2, CCL22, and CCL5 in HaCaT keratinocytes; CCL2, IL-6, and IL-8 in NHDF fibroblasts; and IL-8 in VK2 cells. DHPV showed a favorable safety profile at the tested concentrations and markedly enhanced keratinocyte migration, indicating pro-regenerative activity. Metabolomic analysis revealed effects on tyrosine, histidine, and tryptophan metabolism, pathways related to cell proliferation, migration, and antioxidant defense. Overall, DHPV demonstrated anti-inflammatory and pro-healing properties, supporting its potential as a bioactive compound for inflammatory skin and mucosal conditions.