Downregulated TFPI2 accelerates skin aging by repressing cell cycle via PI3K/Akt/CDC6 pathway.

Tissue factor pathway inhibitor 2 (TFPI2) is known to regulate the proliferation of various cell types and tumor tissues; however, its role in the process of skin aging has not been elucidated. In this study, we identify TFPI2 as a potential antagonist of aging. Our findings indicate that TFPI2 expression is downregulated in aging skin tissues and senescent human dermal fibroblasts (HDFs), and that the depletion of TFPI2 accelerates the senescence of HDFs and the aging of skin. Mechanistically, RNA-seq analysis identifies that cell division cycle 6 (CDC6), a protein associated with the cell cycle, acts as a downstream target of TFPI2. Further liquid chromatography-mass spectrometry (LC-MS) analysis confirmed that TFPI2 interacts with p85β to activate the PI3K/Akt pathway. Subsequent experiments revealed that the activation of the PI3K/Akt pathway alleviates mitigates senescence in HDFs by promoting CDC6 expression and facilitating cell cycle progression. Collectively, these findings underscore the crucial role of the TFPI2/PI3K/Akt/CDC6 pathway in the process of skin aging, highlighting its potential in the development of anti-aging interventions.