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

Fan Wang; Caitan Yi; Yun Zhong; Lei Zhou; Xin Meng; Rui Mao; Yi Guo; Hongfu Xie; Yiya Zhang; Yingxue Huang; Ji Li

doi:10.1016/j.jid.2024.11.028

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

J Invest Dermatol. 2025 Jan 21:S0022-202X(25)00033-8. doi: 10.1016/j.jid.2024.11.028. Online ahead of print.

Authors

Fan Wang¹, Caitan Yi¹, Yun Zhong², Lei Zhou³, Xin Meng¹, Rui Mao¹, Yi Guo¹, Hongfu Xie¹, Yiya Zhang¹, Yingxue Huang⁴, Ji Li⁵

Affiliations

¹ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
² Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China; Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
³ Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China; Department of Dermatology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.
⁴ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China. Electronic address: huangyingxue@csu.edu.cn.
⁵ Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China. Electronic address: liji_xy@csu.edu.cn.

PMID: 39848565
DOI: 10.1016/j.jid.2024.11.028

Abstract

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.

Keywords: CDC6; Celluar Senescence; PI3K/Akt; Skin aging; TFPI2.