2. Academic Validation
  3. Zuogui pill ameliorates DNA damage and the senescence-associated secretory phenotype in ovarian stem cells to delay ovarian ageing through activation of SIRT1

Zuogui pill ameliorates DNA damage and the senescence-associated secretory phenotype in ovarian stem cells to delay ovarian ageing through activation of SIRT1

  • Phytomedicine. 2026 Jun:155:158114. doi: 10.1016/j.phymed.2026.158114.
Yi-Xuan Wang 1,  Yun-Shuo Zhang 2,  Xin Liu 3,  Jun-Yi An 1,  Guan-Ying Li 4,  Yu-Xin Zou 1,  Yun-Ling Zheng 1,  Yuan Fang 5,  Kai-Xuan Li 4,  Ling Zhu 6
Affiliations

Affiliations

  • 1 Guangzhou University of Chinese Medicine, Guangzhou 510407, China; The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangdong Provincial Clinical Research Academy of Chinese Medicine, Guangzhou 510407, China.
  • 2 Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Science and Technology Innovation Center of Guangzhou University of Chinese Medicine, Guangzhou 510407, China.
  • 3 Guangzhou University of Chinese Medicine, Guangzhou 510407, China; School of Basic Medical Sciences,Guangzhou University of Chinese Medicine, Guangzhou 510407, China; State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou 510407, China.
  • 4 Guangzhou University of Chinese Medicine, Guangzhou 510407, China; The Fifth Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510407, China.
  • 5 Guangzhou University of Chinese Medicine, Guangzhou 510407, China; The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510407, China.
  • 6 Lingnan Medical Research Center, Guangdong Provincial Clinical Research Academy of Chinese Medicine, Guangzhou 510407, China; Department of Gynecology, First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510407, China. Electronic address: [email protected].
PMID: 41935462 DOI: 10.1016/j.phymed.2026.158114
Abstract

Background: Ovarian aging, which progresses faster than overall organismal aging, represents a major public health challenge, profoundly impacting female reproductive health and accelerating societal aging. The traditional Chinese medicine formula Zuogui Pill (ZGP) has shown great potential in delaying ovarian aging, warranting further investigation and development.

Purpose: This study sought to elucidate the key molecular targets and underlying mechanisms through which ZGP exerts its protective effects against ovarian aging.

Study design and methods: 8-month-old ovarian aging mice and D-galactose (D-gal)-induced ovarian stem cells (OSCs) were used as models. Phenotypic changes were assessed by hematoxylin-eosin staining, immunofluorescence, flow cytometry, Western blotting, and qPCR. An integrative approach combining transcriptomic profiling, weighted gene co-expression network analysis (WGCNA), network pharmacology, and molecular validation was employed to unravel the underlying mechanisms.

Results: ZGP significantly enhanced the stemness of OSCs in ovarian aging mice, increased follicle numbers, and elevated serum AMH and E2 levels. Findings from integrated bioinformatics and pharmacological analyses point to SIRT1-mediated regulation of DNA damage and the senescence-associated secretory phenotype (SASP) as central to the protective actions of ZGP. Subsequent in vivo and in vitro experiments confirmed that ZGP upregulated SIRT1, suppressed γ-H2AX and CHEK2-mediated DNA damage signaling, modulated the acetylation levels of Ku70 and p65, reduced p53/p21 expression, alleviated SASP, and decreased OSC Apoptosis.

Conclusion: ZGP delays ovarian aging by a SIRT1-dependent mechanism, improving DNA damage repair and alleviating SASP to preserve OSC stemness. These findings provide experimental evidence and mechanistic insight into the potential application of ZGP in delaying ovarian functional decline.

Keywords

DNA damage; Ovarian aging; Ovarian stem cells; SASP; SIRT1; Zuogui Pill.

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