Abstract

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 identified TFPI2 as a potential antagonist of aging. Our findings indicate that TFPI2 expression is downregulated in aging skin tissues and senescent human dermal fibroblasts and that the depletion of TFPI2 accelerates the senescence of human dermal fibroblasts and skin aging. RNA-sequencing analysis revealed that CDC6, a protein associated with cell cycle, is a downstream target of TFPI2. Further liquid chromatography-mass spectrometry analysis confirmed that TFPI2 interacts with p85β to activate the phosphoinositide 3-kinase/protein kinase B pathway. Subsequent experiments revealed that the activation of the phosphoinositide 3-kinase/protein kinase B pathway alleviates senescence in human dermal fibroblasts by promoting CDC6 expression and facilitating cell cycle progression. Collectively, these findings underscore the crucial role of the TFPI2/phosphoinositide 3-kinase/protein kinase B/CDC6 pathway in skin aging and highlight its potential for the development of antiaging interventions.