Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Zuogui pill ameliorates DNA damage and the senescence-associated secretory phenotype in ovarian stem cells to delay ovarian ageing through activation of SIRT1.
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Wang Yi-Xuan, Zhang Yun-Shuo, Liu Xin, An Jun-Yi, Li Guan-Ying, Zou Yu-Xin, Zheng Yun-Ling, Fang Yuan, Li Kai-Xuan, Zhu Ling
Аннотация
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.
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.