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Background: Terminalia chebula (TC) is a deciduous tree of which extracts have demonstrated efficacy for treatment of photodamage, skin aging, and wound healing. However, molecular and cellular mechanisms underlying these benefits remain unclear. Objective: To profile dermal expression responses to a standardized tannin-enriched TC fruit extract (Synastol® TC). Materials and Methods: Microarrays were used to evaluate gene expression in three-dimensional reconstituted human skin cultures. Results: Genome-wide expression responses to TC were the opposite to those observed in cells exposed to oxidative stress, solar-simulated UV radiation, and wounding, with increased expression of genes associated with water homeostasis, skin barrier establishment, blood vessel development, and circadian rhythms. TC also increased expression of extracellular matrix components, such as collagens ( COL1A1, COL1A2) and proteoglycans ( PRELP, OGN), and in separate assays, we showed that TC inhibits MMP enzymes (MMP-1, MMP-2, MMP-3, MMP-9, MMP-12) and microbial activity ( S. aureus, P. acnes). Unexpectedly, mRNA and protein levels of late keratinocyte (KC) differentiation markers ( FLG, LOR) were increased by TC, and expression responses in skin cultures broadly resembled those that occur with KC differentiation. Consistent with these results, TC increased expression of transcription factors regulating KC differentiation ( FOS, GHRL3, PPARG) and we noted enrichment of AP-1 binding sites in regions upstream of TC-increased genes. Conclusion: These results demonstrate that functionally important TC extract responses occur in the epidermis and are therefore not restricted to the dermal layer. Our findings thus suggest mechanisms by which TC may strengthen full-thickness skin architecture for treatment of skin aging and/or chronic wounds.