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CM-37

Targeting HIF-1α with astragaloside IV overcomes paracrine senescent cells

by exosome from primary senescent cells driven by pro-ferroptotic signaling

in skin aging

1
Shang-Chuan Ng (黃襄川), Chih-Yang Huang (黃志揚), 2,3,4,5 , Wei-Wen Kuo (郭薇雯)* ,1,6,7

1 Department of Biological Science and Technology, China Medical University, Taichung,
Taiwan.
2 Department of Medical Research, China Medical University Hospital, China Medical
University, Taichung, Taiwan.
3 Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung,
Taiwan.
4 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
5 Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi
Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
6 Ph.D. Program for Biotechnology Industry, China Medical University, Taichung 406, Taiwan.
7 School of pharmacy, China Medical University, Taichung, Taiwan.
* E-mail: wwkuo@mail.cmu.edu.tw

Abstract
Primary senescent cells (Sc) secrete senescence-associated secretory phenotypes (SASPs),
which influence neighboring cells, including young skin cells, contributing to the accumulation
of paracrine senescent cells (PSc) with advancing age. Hypoxia-inducible factor-1α (HIF-1α)
plays a critical role in activating downstream genes that preserve skin integrity; however, its
specific function in aged human dermal fibroblasts (HDFs) remains insufficiently understood.
While ferroptosis has been implicated as a key driver of cellular senescence, its exact role in
skin aging requires further elucidation. Astragaloside IV (AST-IV), a bioactive compound
derived from the traditional Chinese medicinal herb Astragalus propinquus (RAP, 黃耆),
shows potential as a HIF-1α activator and whether it can exert anti-skin aging effect is
interesting. Our results show reduced HIF-1α levels in aged HDFs and sun-exposed human skin
tissues, coupled with acceleration of cellular aging by diminished HIF-1α expression and the
next-generation sequencing (NGS) data suggesting that ferroptosis plays a significant role in
skin aging. Furthermore, our results showed the anti-aging effects of RAP and AST-IV were
through stabilizing HIF-1α to attenuate ferroptosis in aged-HDFs in vitro and promoting skin
rejuvenation and wound healing in vivo. This study offer compelling evidence that AST-IV,
acting as a HIF-1α activator, holds potential as a valuable supplement for cosmetic applications
targeting skin aging and promoting dermal health.

Keywords: HIF-1α; Ferroptosis; Astragaloside IV; Skin Aging; Exosomes