Urolithin A Protects Ovarian Reserve Via Inhibiting PI3K/Akt Signaling and Preventing Chemotherapy-Induced Follicle Apoptosis

TL;DR

Urolithin A, a gut metabolite, protects ovarian reserve by inhibiting cell signaling and reducing chemotherapy-induced follicle death, potentially preserving fertility in cancer patients.

Contribution

The study reveals Urolithin A's novel ability to inhibit PI3K/Akt signaling and reduce chemotherapy-induced apoptosis in ovarian follicles.

Findings

Urolithin A inhibits primordial follicle activation by downregulating PI3K/Akt signaling.

Urolithin A reduces chemotherapy-induced follicle apoptosis by decreasing DNA damage and apoptosis markers.

RNA-seq analysis shows Urolithin A downregulates DNA damage-related genes like Trp73 and Trim29.

Abstract

Urolithin A, which is a gut-derived metabolite, demonstrates broad therapeutic potential through lifespan extension, disease mitigation, oocyte quality improvement, and detoxification effects. In the study, Urolithin A inhibited granulosa cell proliferation, downregulated key oocyte growth signals (Gdf9, Zp3, and DDX4), and blocked PI3K/Akt signaling reactivity, which helps maintain primordial follicle dormancy. It also reduced cyclophosphamide (CY) and 4-hydroperoxy (4-HC)-induced follicle loss by decreasing DNA damage markers (Trp73 and Trim29) and apoptosis signals (Caspase-3 and PARP1). These findings suggest that Urolithin A could help preserve fertility in women undergoing chemotherapy.

Urolithin A, which is a natural gut microbial metabolite, exerts multiple beneficial effects upon supplementation, including prolonging lifespan, mitigating diseases, restoring the quality of aged oocytes and alleviating drug toxicity. The study aims to investigate the ovarian protective role of Urolithin A using a neonatal mouse ovarian in vitro culture and chemotherapy model, with a particular focus on its mechanisms for inhibiting primordial follicle activation and mitigating cyclophosphamide (CY) or 4-hydroperoxy (4-HC)-induced follicle apoptosis. The results showed that Urolithin A significantly decreased the number of growing follicles and downregulated the expression of oocyte growth-related genes (Gdf9 and Zp3) and protein (DDX4), as well as Ki-67 and BrdU-positive signals. Further studies revealed that Urolithin A significantly downregulated the levels of phosphorylated Akt and FOXO3a and decreased the percentage of oocytes with FOXO3a nuclear export. Molecular docking showed a strong binding ability between Urolithin A and its downregulated gene Pik3cg. Moreover, Urolithin A significantly decreased CY- and 4-HC-induced increases in cleaved Caspase-3- and PARP1-positive signals. Meanwhile, RNA-seq analysis indicated that Urolithin A significantly downregulated CY-induced expression of DNA damage-related genes (Trp73 and Trim29). In short, Urolithin A inhibits primordial follicle activation by reducing PI3K/Akt signaling reactivity. Furthermore, Urolithin A prevents CY-induced follicle apoptosis. The study provides valuable insights into Urolithin A treatment for chemotherapy-induced infertility.

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