Eupatilin (5,7-dihydroxy-3,4,6-trimethoxyflavone) is a flavonoid compound exhibiting several beneficial biological activities, including neuroprotection, anti-cancer, antinociception, chondroprotection, anti oxidation, and anti-inflammation. Our previous study demonstrated that eupatilin specifically activates peroxisome proliferator-activated receptor alpha (PPAR alpha) through direct binding. The PPAR subfamily includes ligand-dependent transcription factors that consist of three isotypes: PPAR alpha, PPAR beta/delta, and PPAR gamma. All isotypes are involved in inflammation, epidermal proliferation/differentiation and skin barrier function. Among them, PPAR alpha regulates lipid and glucose metabolism and skin homeostasis. In this study, we confirm that the ability of eupatilin as a PPAR alpha activator significantly inhibited tumor necrosis factor-alpha (TNF alpha)-induced matrix metalloproteinase (MMP)-2/-9 expression and proteolytic activity in HaCaT human epidermal keratinocytes. Furthermore, we found that eupatilin subsequently suppressed I kappa B alpha phosphorylation, blocked NF-kappa B p65 nuclear translocation and down-regulated MAPK/AP-1 signaling via PPAR alpha activation. Taken together, our data suggest that eupatilin inhibits TNF alpha-induced MMP-2/-9 expression by suppressing NF-kappa B and MAPK/AP-1 pathways via PPAR alpha. Our findings suggest the usefulness of eupatilin for preventing skin aging. (C) 2017 Elsevier Inc. All rights reserved.