Background <p>We previously demonstrated that <i>Artemisia capillaris</i> flower extract (ACFE) suppresses the expression of HYBID (hyaluronan-binding protein involved in hyaluronan depolymerization), a hyaluronan-degrading enzyme, and increases the expression of miR-486-5p, a microRNA that downregulates HYBID. In the same study, we isolated two novel active compounds, Kawarayomogin I and II, and reported that they also suppress HYBID expression. However, it remained unclear whether their inhibitory effects on HYBID were mediated through miR-486-5p. Furthermore, because ACFE has been reported to inhibit melanin production, and miR-141-3p and miR-200a-3p are known to regulate melanogenesis, we investigated whether these compounds modulate melanogenesis-related microRNAs.</p> Methods and Results <p>The expressions levels of miR-486-5p in normal human dermal fibroblasts (NHDF) and miR-141-3p and miR-200a-3p in mouse B16 melanocytes were measured by RT-PCR. Melanin content was quantified by lysing the cells using NaOH followed by taking of absorbance at 420&#xa0;nm. We confirmed for the first time that Kawarayomogin I and II significantly increased the expression of miR-486-5p in NHDF. Among miR-141-3p and miR-200a-3p, ACFE and Kawarayomogin I and II selectively induced miR-141-3p in B16. These findings identify Kawarayomogin I and II as the principal active components responsible for the melanin-suppressing activity of ACFE for the first time. Although these compounds may influence other microRNAs, our results suggest that they selectively regulate miR-486-5p and miR-141-3p, indicating an epigenetic mechanism underlying their biological effects.</p> Conclusions <p>Collectively, Kawarayomogin I and II represent promising bioactive molecules that selectively and epigenetically regulate microRNA expression to confer dual functions in hyaluronan protection and melanogenesis suppression.</p>