Placental Extracellular Vesicles Inhibit the Progression of Endometriosis by Inducing Ferroptosis

Endometriosis (EMs) is an estrogen-dependent chronic inflammatory disease, and its pathogenesis remains unclear. Although the placenta is an organ with tumor-like characteristics, its development, including its invasive function, is tightly controlled. One of the mechanisms is that extracellular vesicles (EVs) released by the placenta play an important role in this regulation. Placental extracellular vesicles carry functional proteins and regulatory RNAs. Our previous studies reported that placental extracellular vesicles inhibit the growth of ovarian cancer and cervical cancer both in vitro and in vivo. In recent years, ferroptosis, a novel form of cell death driven by iron-dependent lipid peroxidation, has been found to play a key role in the development of EMs.

Extracellular vesicles (EVs) derived from the placenta were isolated and identified, and their morphology and size distribution were characterized by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA).In vitro experiments were conducted using endometriosis cells as a model. Cell viability was assessed using the CCK-8 assay. The expression of the ferroptosis-related molecules GPX4 and SLC7A11 was detected by Western blot and qRT-PCR, while lipid peroxidation and oxidative stress were evaluated by measuring malondialdehyde (MDA) and reactive oxygen species (ROS) levels. In addition, the ferroptosis inhibitor Ferrostatin-1 (Fer-1) was used for intervention experiments to verify the role of ferroptosis in this process. Potential miRNAs were further predicted using bioinformatic databases, and the regulatory mechanism was validated through miRNA transfection experiments, dual-luciferase reporter assays, and SLC7A11 overexpression rescue experiments. In vivo, a mouse model of endometriosis was established to evaluate the effect of EVs on the growth of ectopic lesions.

The current study demonstrated that placental EVs delivered miRNA-26a-5p, which downregulated SLC7A11, led to increased lipid peroxidation and triggered ferroptosis, and ultimately inhibited the progression of endometriosis. Fer-1 effectively reversed these effects. In vivo, placental EVs significantly reduced ectopic lesion volume in mice.

This study revealed that placental EVs induced ferroptosis through miRNA-26a-5p/SLC7A11-GPX4 axis, providing a potential therapeutic target for endometriosis.