PMEPA1-Mediated Treg Cell Impairment Promotes Endometrial Stromal Invasion via Excessive PI3K/AKT Signaling in Endometriosis

Objective Although immune dysregulation is implicated in the pathogenesis of endometriosis (EMs), the specific role of prostate transmembrane protein androgen induced 1 (PMEPA1) in modulating the function of regulatory T cells (Tregs) remains inadequately understood. This study aimed to elucidate the regulatory mechanisms by which PMEPA1 influences the activity of Tregs, thereby facilitating the invasion of endometrial stromal cells (ESCs).

Single-cell RNA sequencing (scRNA-seq) was performed on matched ectopic ovarian lesions and eutopic endometria from 3 patients. Clinical specimens from patients with EMs and control subjects were examined for PMEPA1 expression. Primary human Tregs isolated from peripheral blood mononuclear cells were subjected to PMEPA1 overexpression (via plasmid) or knockdown (via siRNA). Modulation of the PI3K pathway was conducted via the activator 740Y-P or the inhibitor LY294002. The secretion of IL-10 and TGF-β by Tregs was quantified using an enzyme-linked immunosorbent assay. Ectopic ESCs cocultured with modified Tregs were assessed for their proliferation, migration, and invasion capabilities.

scRNA-seq data revealed significant upregulation of PMEPA1 in Tregs from ectopic ovarian lesions compared with paired eutopic endometria. PMEPA1 expression was increased in the ectopic lesions and peritoneal fluid mononuclear cells of patients with EMs. Tregs overexpressing PMEPA1 demonstrated reduced secretion of IL-10 and TGF-β but exhibited hyperactivation of the PI3K/AKT signaling pathway. Treatment with LY294002 ameliorated the impairment in cytokine secretion. Coculture experiments with Tregs expressing high levels of PMEPA1 resulted in increased invasion, migration, and proliferation of ESCs.

PMEPA1 impairs Treg-mediated immunosuppression by hyperactivating the PI3K/AKT pathway, thereby facilitating the invasiveness of ESCs in EMs. Similar content being viewed by others Availability of Data and Materials All the data and study materials used in the current study are available from the corresponding authors on reasonable request.

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Not applicable. Funding Not applicable. Author information Authors and Affiliations Contributions Ya-qin Peng: Writing original draft and project administration. Lu Wang, Ai-li Tan, Shu-jun Wang and Wen Zou: Resources and sample collection; Xing Li: Resources and review & editing. Jing Yang: Supervision and funding acquisition. All authors read and approved the manuscript. Corresponding authors Ethics declarations Ethics Approval and Consent to Participate The study protocol was approved by the Institutional Review Board of Renmin Hospital of Wuhan University (Approve No. WDRY2024-K111). Written informed consent was obtained from all participants. Consent for Publication All participants agree to the publication of the article. Competing Interests On behalf of all authors, the corresponding author states that there is no conflict of interest. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Peng, Yq., Wang, L., Tan, Al. et al. PMEPA1-Mediated Treg Cell Impairment Promotes Endometrial Stromal Invasion via Excessive PI3K/AKT Signaling in Endometriosis. CURR MED SCI 45, 1231–1243 (2025). https://doi.org/10.1007/s11596-025-00125-0 Received: Revised: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s11596-025-00125-0