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. 2025 May 20;138(10):1225-1235.
doi: 10.1097/CM9.0000000000003127. Epub 2024 May 9.

SIRT3 protects endometrial receptivity in patients with polycystic ovary syndrome

Zhonghong Zeng  1   2   3   4   5 , Hongying Shan  1   2   3   4   6 , Mingmei Lin  1   2   3   4 , Siyu Bao  1   2   3   4 , Dan Mo  1   2   3   4   5 , Feng Deng  1   2   3   4 , Yang Yu  1   2   3   4 , Yihua Yang  5 , Ping Zhou  1   2   3   4 , Rong Li  1   2   3   4
Affiliations

SIRT3 protects endometrial receptivity in patients with polycystic ovary syndrome

Zhonghong Zeng et al. Chin Med J (Engl). .

Abstract

Background: The sirtuin family is well recognized for its crucial involvement in various cellular processes. Nevertheless, studies on its role in the human endometrium are limited. This study aimed to explore the expression and localization of the sirtuin family in the human endometrium, focusing on sirtuin 3 (SIRT3) and its potential role in the oxidative imbalance of the endometrium in polycystic ovary syndrome (PCOS).

Methods: Endometrial specimens were collected from both patients with PCOS and controls undergoing hysteroscopy at the Center for Reproductive Medicine, Peking University Third Hospital, from July to August 2015 and used for cell culture. The protective effects of SIRT3 were investigated, and the mechanism of SIRT3 in improving endometrial receptivity of patients with PCOS was determined using various techniques, including cellular bioenergetic analysis, small interfering ribonucleic acid (siRNA) silencing, real-time quantitative polymerase chain reaction, Western blot, immunofluorescence, immunohistochemistry, and flow cytometry analysis.

Results: The sirtuin family was widely expressed in the human endometrium, with SIRT3 showing a significant increase in expression in patients with PCOS compared with controls ( P <0.05), as confirmed by protein and gene assays. Concurrently, endometrial antioxidant levels were elevated, while mitochondrial respiratory capacity was reduced, in patients with PCOS ( P <0.05). An endometrial oxidative stress (OS) model revealed that the downregulation of SIRT3 impaired the growth and proliferation status of endometrial cells and reduced their receptivity to day 4 mouse embryos. The results suggested that SIRT3 might be crucial in maintaining normal cellular state by regulating antioxidants, cell proliferation, and apoptosis, thereby contributing to enhanced endometrial receptivity.

Conclusions: Our findings proposed a significant role of SIRT3 in improving endometrial receptivity in patients with PCOS by alleviating OS and regulating the balance between cell proliferation and apoptosis. Therefore, SIRT3 could be a promising target for predicting and improving endometrial receptivity in this patient population.

Keywords: Apoptosis; Endometrial receptivity; Oxidative stress; Polycystic ovary syndrome; Sirtuin 3.

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Conflict of interest statement

None.

Figures

Figure 1
Figure 1
Expression of sirtuin family member SIRT1–7 in the human endometrium. (A) Sirtuin proteins were expressed in endometrial cells. The green fluorescence visualized these proteins. DAPI was used to visualize the nuclei. Original magnifucation × 63; scale bar = 100 μm. (B) Expression of mRNA of SIRT1–7. (C) Protein levels of SIRT3 in the PCOS and control groups as assessed using Western blotting. (D) Distribution of SIRT3 in the nucleus of PCOS endometrial cells was significantly higher than that in the control group. Scale bar = 100 μm. (E) Immunohistochemical analysis in the PCOS and control groups. Scale bar = 100 μm (*P <0.05 vs. the control group). DAPI: Diamidino-phenyl-indole; GFL: Green fluorescence; mRNA: Messenger RNA; PCOS: Polycystic ovary syndrome; SIRT: Sirtuin.
Figure 2
Figure 2
Elevated levels of antioxidants and decreased mitochondrial respiratory capacity in the endometrium of patients with PCOS. (A) Genes of anti-OS were upregulated in PCOS endometrial tissues. (B,C) OCR of PCOS endometrial cells decreased compared with that in the control group (*P <0.05 vs. the control group). ATP: Adenosine triphosphate; CAT: Catalase; GPx: Glutathione peroxidase; mRNA: Messenger RNA; OCR: Oxygen consumption rate; OS: Oxidative stress; PCOS: Polycystic ovary syndrome; SOD: Superoxide dismutase.
Figure 3
Figure 3
Model of chronic OS in endometrial cells. (A) Control group of endometrial cells. (B) State of the cells after culturing with 125 μmol/L H2O2 for 12 h. No significant abnormality was observed. (C) A large number of cells died after culturing with 500 μmol/L H2O2 for 4 h. (D,E) State of the cells after culturing with 250 μmol/L H2O2 for 4 h and 12 h, respectively. No significant abnormality was observed. Scale bar = 100 μm. The arrow shows cellular oncosis. (F) Apoptosis in the control group. (G,H) Apoptosis of endometrial cells cultured with 250 μmol/L H2O2 for 4 h and 12 h. The apoptosis percentage was 3.03% and 4.92%, respectively. (I) A higher percentage of cell apoptosis was observed when the cells were cultured with 500 μmol/L H2O2 for 4 h, reaching 36.03%. H2O2: Hydrogen peroxide; OS: Oxidative stress.
Figure 4
Figure 4
Expression of related factors was evaluated after exposure of endometrial cells to 250 μmol/L H2O2 for 4 h and 12 h. (A–C) Endometrial cells cultured using 250 μmol/L H2O2 for 4 h. The expression of anti-OS markers and SIRT3–5 was not significantly different between the OS and control groups. (D–F) Endometrial cells cultured with 250 μmol/L H2O2 for 12 h. The expression of anti-OS markers was upregulated, and the expression of SIRT3 significantly increased in the OS group compared with the control group (*P <0.01 vs. the control group). CAT: Catalase; GPx: Glutathione peroxidase; H2O2: Hydrogen peroxide; OS: Oxidative stress; SOD: Superoxide dismutase.
Figure 5
Figure 5
Expression of related functions was evaluated after exposure of endometrial cells to 250 μmol/L H2O2 for 12 h. Embryos from both the non-adhesion (A1) and adhesion groups (A2) interacting with endometrial cells in the control group. Embryos of non-adhesion (A3) and adhesion groups (A4) interacting with OS endometrial cells. (B) Adhesion rate of embryos to OS endometrial cells was not significantly different from that in the control group. (C) OCR curve of endometrial cells in the OS and control groups. (D) Basal respiration, ATP production, maximal respiration, and spare capacity of the OS group significantly decreased compared with that in the control group (*P <0.001 vs. the control group). ATP: Adenosine triphosphate; H2O2: Hydrogen peroxide; OCR: Oxygen consumption rate; OS: Oxidative stress.
Figure 6
Figure 6
SIRT3 protected the endometrial receptivity by anti-OS. (A) Control group with non-implanted (A1) and implanted embryos (A2). (B) SIRT3 RNAi endometrial cells with non-implanted (B1) and implanted embryos (B2). (C) Embryonic adhesion rate of endometrial cells in the SIRT3 RNAi group was 58.89%, which was significantly lower than the adhesion rate of 73.86% in the control group. (D) Endometrial cells in the control group. (E) Expression of SIRT3 in endometrial cells was significantly inhibited by siRNA. (F) Endometrial cells of SIRT3 RNAi. (G) Apoptotic rate of SIRT3 RNAi endometrial cells significantly increased compared with that in the control group. (G1) Control group. (G2) SIRT3 RNAi group. (H) Expression of markers of anti-OS, such as CAT, SOD, and GPx, significantly decreased after treatment with SIRT3 RNAi. The apoptosis pathway was significantly activated after treatment with SIRT3 RNAi. P53 and p21 were the factors promoting apoptosis, whereas Bcl2 was an anti-apoptotic factor (scale bar = 100 μm, *P <0.05, †P <0.01 vs. the control group). Bcl2: B-Cell lymphoma 2; CAT: Catalase; GPx: Glutathione peroxidase; OS: Oxidative stress; RNAi: RNA interference; SIRT3: Sirtuin 3; siRNA: Small interfering ribonucleic acid; SOD: Superoxide dismutase.
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