Decoding skin aging: the role of KNG1 in collagen and elastic fibre degradation.

Kininogen-1 (KNG1) is an important pro-inflammatory and pro-oxidant factor, but its precise role in skin aging remains inadequately elucidated. Quantitative 4D proteomic-sequencing analysis identified upregulated KNG1 in 3- and 15-month-old C57BL/6J mouse skin, with immunohistochemical staining corroborating its increase in intrinsic aging. KNG1 overexpression in murine skin reduced dermal thickness, collagen fibre content, elastic fibre density, aging marker Lamin B1, and increased oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), while KNG1 knockdown ameliorated these aging-associated phenotypes. Protein-protein interaction analysis revealed the underlying mechanisms. KNG1 regulates elastic fibre degradation through membrane metallo-endopeptidase (MME) activity, modulates collagen fibre degradation via matrix metallopeptidase 1 (MMP1) and matrix metallopeptidase 9 (MMP9), and elevates oxidative stress through epoxide hydrolase 2 (EPHX2). Thus, KNG1 may serve as an intrinsic skin aging biomarker, promoting collagen fibre degradation through MMP1/MMP9, elastic fibre breakdown through MME, and oxidative stress through EPHX2. KNG1 downregulation may represent a prospective anti-aging target.