ROBO3 Drives Endometriosis Progression via Dual Wnt/β-Catenin Activation and M2 Macrophage Polarization

Xinyue Zhou, Zhou X, Wei Zhou, Zhou W, Changhong Qu, Qu C, Jiang Y, Yisha Jiang, Liu W, Wenzhu Liu, Lipeng Pei, Pei L
Biological & pharmaceutical bulletin · 2025 · vol. 48(10) , pp. 1503–1513 · doi:10.1248/bpb.b25-00262 · PMID:41083379
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⚙ AI-generated summary by claude@2026-07, 2026-07-28 ⓘ

This study found that ROBO3 drives endometriosis progression by activating Wnt/β-catenin signaling and promoting M2 macrophage polarization through CCL2 and CCL5 secretion.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-13 · read from full text ⓘ

The paper investigates whether roundabout guidance receptor 3 (ROBO3) contributes to endometriosis progression and, if so, through which mechanisms. Using bioinformatics, the authors report abnormally high ROBO3 expression in endometriosis, and in vitro functional assays show that ROBO3 promotes invasion and migration of endometriotic stromal cells. Mechanistically, ROBO3 activates Wnt/β-catenin signaling, supported by increased GSK3β phosphorylation, nuclear β-catenin accumulation, and higher c-myc expression; Wnt/β-catenin inhibition with MSAB reverses ROBO3-driven pro-invasive and pro-migratory effects, with the study primarily limited to these in vitro and pathway-based experiments. ROBO3 also increases ESC secretion of CCL2 and CCL5, which correlates with M2 macrophage polarization marked by elevated IL-10 and Arg-1. This paper is centrally about endometriosis — it identifies ROBO3 as a driver of endometriosis-associated stromal cell invasion/migration via dual Wnt/β-catenin activation and macrophage M2 polarization.

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Abstract

Endometriosis, a prevalent gynecological disorder marked by ectopic growth of endometrial-like tissue, demonstrates malignant tumor-like properties including aggressive adhesion and invasiveness. Emerging evidence implicates roundabout guidance receptor 3 (ROBO3) in cellular pathophysiology, yet its role in endometriosis remains unexplored. In this study, we first found abnormally high ROBO3 expression in endometriosis by bioinformatics analysis. Next, functional assays revealed that ROBO3 is a key regulator promoting the invasion and migration of endometriotic stromal cells (ESCs) in vitro. Mechanistically, ROBO3 activates the Wnt/β-catenin signaling pathway, evidenced by increased phosphorylation of glycogen synthase kinase 3β, nuclear β-catenin accumulation, and upregulated c-myc expression. Pharmacological inhibition of Wnt/β-catenin with MSAB (5 μM) reversed ROBO3-mediated pro-invasive and pro-migratory effects. Furthermore, we discovered that ROBO3 enhances the secretion of chemokines CCL2 and CCL5 in ESCs, which subsequently promote macrophage polarization toward the M2 phenotype, as indicated through elevated expression of interleukin-10 and Arg-1. Collectively, our findings elucidate a dual mechanism whereby ROBO3 drives endometriosis progression through both intrinsic activation of Wnt/β-catenin signaling and extrinsic modulation of tumor-associated macrophages, underscoring ROBO3 as a promising therapeutic target for endometriosis.
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Keywords

endometriosis, roundabout guidance receptor 3, macrophage polarization, Wnt/β-catenin pathway 2025 Volume 48 Issue 10 Pages 1503-1513 Details

Abstract

Endometriosis, a prevalent gynecological disorder marked by ectopic growth of endometrial-like tissue, demonstrates malignant tumor-like properties including aggressive adhesion and invasiveness. Emerging evidence implicates roundabout guidance receptor 3 (ROBO3) in cellular pathophysiology, yet its role in endometriosis remains unexplored. In this study, we first found abnormally high ROBO3 expression in endometriosis by bioinformatics analysis. Next, functional assays revealed that ROBO3 is a key regulator promoting the invasion and migration of endometriotic stromal cells (ESCs) in vitro. Mechanistically, ROBO3 activates the Wnt/β-catenin signaling pathway, evidenced by increased phosphorylation of glycogen synthase kinase 3β, nuclear β-catenin accumulation, and upregulated c-myc expression. Pharmacological inhibition of Wnt/β-catenin with MSAB (5 μM) reversed ROBO3-mediated pro-invasive and pro-migratory effects. Furthermore, we discovered that ROBO3 enhances the secretion of chemokines CCL2 and CCL5 in ESCs, which subsequently promote macrophage polarization toward the M2 phenotype, as indicated through elevated expression of interleukin-10 and Arg-1. Collectively, our findings elucidate a dual mechanism whereby ROBO3 drives endometriosis progression through both intrinsic activation of Wnt/β-catenin signaling and extrinsic modulation of tumor-associated macrophages, underscoring ROBO3 as a promising therapeutic target for endometriosis. © 2025 Author(s). Published by The Pharmaceutical Society of Japan Published by The Pharmaceutical Society of Japan This article is licensed under a Creative Commons [Attribution-NonCommercial 4.0 International] license. https://creativecommons.org/licenses/by-nc/4.0/ Favorites & Alerts Recently viewed articles

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endometriosis

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Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis

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