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  3. Platycodin D ameliorates polycystic ovary syndrome-induced ovarian damage by upregulating CD44 to attenuate ferroptosis

Platycodin D ameliorates polycystic ovary syndrome-induced ovarian damage by upregulating CD44 to attenuate ferroptosis

  • Free Radic Biol Med. 2024 Sep 24:224:707-722. doi: 10.1016/j.freeradbiomed.2024.09.033.
Rui Ji 1,  Shujun Wang 2,  Xin Chen 1,  Zhe Yang 1,  Zhimo Zhang 1,  Shenglan Bao 1,  Zhuoni Xiao 3,  Yan Zhang 4,  Tailang Yin 5,  Jing Yang 6
Affiliations

Affiliations

  • 1 Reproductive Medical Center, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China.
  • 2 Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China.
  • 3 Reproductive Medical Center, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China. Electronic address: RM001111@whu.edu.cn.
  • 4 Department of Clinical Laboratory, Renmin Hospital of Wuhan University, WuHan, China. Electronic address: peneyyan@whu.edu.cn.
  • 5 Reproductive Medical Center, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China. Electronic address: reproductive@whu.edu.cn.
  • 6 Reproductive Medical Center, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China. Electronic address: dryangjing@whu.edu.cn.
PMID: 39321891 DOI: 10.1016/j.freeradbiomed.2024.09.033
Abstract

Recently, the potential association between polycystic ovary syndrome (PCOS) development and progression and Ferroptosis has garnered attention. Increasing evidence suggests that targeting Ferroptosis may be an effective strategy for treating PCOS. First, we observed that the expression of the Ferroptosis regulatory molecules SLC7A11, GPX4, and FTH1 was decreased in the granulosa cells (GCs) of patients with PCOS and ovarian tissues of rats with PCOS; in contrast, TFR1 expression was increased. This suggests that GC Ferroptosis is involved in PCOS pathogenesis. Furthermore, bioinformatics analysis of GC datasets from patients with PCOS and PCOS clinical samples and animal model analysis revealed CD44 as a key molecule regulating Ferroptosis in PCOS, which was down-regulated in GCs of PCOS patients and rats. Subsequently, molecular docking was performed to screen existing natural compounds for inhibiting Ferroptosis. Dynamic simulation and cellular thermal shift assay identified platycodin D as a natural plant extract for inhibiting Ferroptosis by targeting CD44 in GCs. Subsequently, a series of functional experiments revealed that platycodin D ameliorated ovarian damage in rats with PCOS. This was primarily owing to the protective effects achieved by promoting glutathione production, attenuating lipid accumulation and lipid peroxidation in GCs, inhibiting iron overload, and scavenging Reactive Oxygen Species. In addition, western blotting and immunofluorescence staining revealed that platycodin D upregulated the expression of CD44 and SLC7A11 in GCs. Furthermore, by knocking down CD44 and SLC7A11 in vivo and in vitro, respectively, the ameliorative effect of platycodin D on Ferroptosis in the GCs of rats with PCOS was reversed. Collectively, these findings suggest that platycodin D attenuates Ferroptosis in GCs by activating CD44/SLC7A11 axis, thereby upregulating system Xc-. In conclusion, platycodin D can attenuate Ferroptosis in GCs by activating CD44, potentially ameliorating ovarian damage in PCOS.

Keywords

CD44; Ferroptosis; Platycodin D; Polycystic ovary syndrome (PCOS).

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