Anti-Skin Aging Potential of Methoxyflavones from Kaempferia parviflora Against TNF-α-Induced Oxidative Stress and Photoaging in Normal Human Dermal Fibroblasts

Reactive oxygen species (ROS) generated by ultraviolet (UV) radiation accelerate skin aging by activating matrix metalloproteinase-1 (MMP-1) and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, antioxidants that can suppress ROS generation and downstream signaling cascades are considered promising anti-aging agents. In this study, five methoxyflavones were isolated from <i>Kaempferia parviflora</i> (black ginger) rhizomes-5,7,3',4'-tetramethoxyflavone (<b>1</b>), 3,5,7,4'-tetramethoxyflavone (<b>2</b>), 5,7,4'-trimethoxyflavone (<b>3</b>), 3,5,7,3',4'-pentamethoxyflavone (<b>4</b>), and 5,7-dimethoxyflavone (<b>5</b>)-using LC-MS-guided fractionation and identified via NMR and LC-MS analysis. Their biological activities were evaluated in tumor necrosis factor-α (TNF-α)-stimulated normal human dermal fibroblasts (NHDFs). All methoxyflavones, except compound <b>3</b>, significantly suppressed TNF-α-induced ROS generation, while compounds <b>3</b>-<b>5</b> markedly reduced MMP-1 secretion. Among them, compounds <b>4</b> and <b>5</b> exerted the strongest protective effects by modulating distinct MAPK pathways: compound <b>4</b> selectively inhibited p38 phosphorylation, whereas compound <b>5</b> selectively suppressed ERK phosphorylation. Both compounds attenuated ECM degradation and enhanced antioxidant defenses in a concentration-dependent manner. Collectively, these findings highlight the mechanistic significance of methoxyflavones <b>4</b> and <b>5</b> as dual-acting antioxidant and ECM-protective agents that counteract skin aging through selective regulation of MAPK signaling. Their potential as natural anti-photoaging ingredients warrants further validation in in vivo models and clinical studies for future skincare applications.