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 Kaempferia parviflora (black ginger) rhizomes—5,7,3′,4′-tetramethoxyflavone (1), 3,5,7,4′-tetramethoxyflavone (2), 5,7,4′-trimethoxyflavone (3), 3,5,7,3′,4′-pentamethoxyflavone (4), and 5,7-dimethoxyflavone (5)—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 3, significantly suppressed TNF-α-induced ROS generation, while compounds 3–5 markedly reduced MMP-1 secretion. Among them, compounds 4 and 5 exerted the strongest protective effects by modulating distinct MAPK pathways: compound 4 selectively inhibited p38 phosphorylation, whereas compound 5 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 4 and 5 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.