A novel polypeptide inhibitor of MMP-1 attenuates the UVA-mediated skin aging

Matrix metalloproteinase-1 (MMP-1) plays a crucial role in maintaining skin extracellular matrix (ECM) homeostasis. Its dysregulated activation leads to collagen degradation, reduced skin elasticity, and wrinkle formation during aging. In this study, we evaluated the effects of a novel polypeptide inhibitor, IP10-3 (ISCGNCALMP), targeting MMP-1 in a model of UVA-induced senescence in HFF-1 cells. Treatment with IP10-3 effectively inhibited MMP-1 catalytic activity. In vitro assays demonstrated that IP10-3 treatment decreased the proliferation and increased apoptosis of UVA-induced senescent HFF-1 cells while has no impact on normal HFF-1 cells. qRT-PCR and ELISA analyses further revealed that IP10-3 treatment downregulated the expression of senescence-associated genes and pro-inflammatory cytokines (MMP-1, p21, p16, IL-1β, IL-6, TNF-α), while upregulating ECM proteins such as Collagen I and Collagen III in UVA-exposed HFF-1 cells. In ex vivo human skin models, IP10-3 treatment resulted in reduced wrinkle formation and improved skin firmness. Mechanistically, IP10-3 exerted its anti-aging effects by inhibiting the ROS-mediated inflammatory pathway in UVA-induced senescent HFF-1 cells. These findings highlight the potential of IP10-3 as an effective anti-aging agent and support its further investigation as a therapeutic strategy for skin senescence and aging-related skin disorders caused by ultraviolet radiation.