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Acne vulgaris, typically caused by Cutibacterium acnes (C. acnes) involves chronic inflammation of the sebaceous follicles and is the most common skin disease, afflicting 85% of adolescents. We previously isolated 2 novel phenolic glycosides, 2-caffeoyl-3-hydroxy-3-methylbutyric 4′-β-D-glucopyranosyloxy-3′-hydroxybenzyl ester (citrulluside H [CH]) and 2-caffeoyl-3-hydroxy-3-methylbutyric 4′-β- d -glucopyranosyloxybenzyl ester (citrulluside T [CT]), from young fruits of watermelon (Citrullus lanatus). Both compounds suppressed UVB-induced photoaging in human fibroblasts by scavenging intracellular reactive oxygen species (ROS) and thus might be useful as natural skin care ingredients. In this study, we examined the inhibitory effects of these phenolic glycosides on C. acnes growth and C.acnes- induced inflammation. Neither phenolic glycoside inhibited the growth of C. acnes. However, they both significantly suppressed toll-like receptor (TLR) 1/2 or TLR2/6/nuclear factor κB (NF-κB) signaling in heat-killed C. acnes (hk- C. acnes) - stimulated RAW264.7 cells. Additionally, both phenolic glycosides decreased the expression of M1 macrophage biomarkers (cluster of differentiation [ CD ] 80, CD86, and inducible NO synthase [ iNOS ]), suggesting that they attenuate M1 macrophage activation. These results indicated that both CH and CT are potential therapeutic substances against C. acnes -induced skin inflammation. [ABSTRACT FROM AUTHOR]