ACSL4 overexpression disrupts endometrial receptivity in endometriosis (EMs) patients and mouse models.

PRGL493 (ACSL4 inhibitor) reduces ectopic lesions and lipid peroxidation in EMs mice.

PRGL493 restores pinopode formation and receptivity markers (αVβ3/OPN/HOXA10) in EMs mice.

Human endometrial organoids reveal PRGL493 rescues secretory-phase ultrastructural defects.

First evidence linking ACSL4-mediated ferroptosis to EMs endometrial receptivity.

This study investigated the role of ACSL4 in endometrial receptivity disorders in endometriosis (EMs) and evaluated PRGL493, an ACSL4 inhibitor, as a potential therapeutic target. Bioinformatic analysis identified ACSL4 as a potential key regulator among ferroptosis and receptivity-related genes. Clinical samples from EMs patients showed significantly higher endometrial ACSL4 expression and lower receptivity marker expression (αVβ3, OPN, HOXA10) compared to controls. In a mouse EMs model, PRGL493 treatment reduced lesion volume, decreased lipid peroxidation, increased pinopode formation, and improved expression of receptivity markers. Similarly, in human endometrial organoids from EMs patients, PRGL493 ameliorated ultrastructural abnormalities, including mitochondrial condensation, decreased secretory granules, and endoplasmic reticulum expansion, and restored receptivity marker expression to levels comparable to the control. These findings demonstrate that ACSL4 overexpression is associated with endometrial receptivity disorders in EMs and that ACSL4 overexpression is a key pathological feature linked to endometrial receptivity impairment in EMs. Targeting ACSL4 with PRGL493 ameliorates receptivity defects, suggesting its therapeutic potential for EMs-associated infertility.

Endometriosis

Ferroptosis marker protein

Endometrial receptivity

ACSL4

© 2025 The Authors. Published by Elsevier B.V.