SPP1 as a key modulator of M2 macrophage polarization promotes endometriosis progression via activation of the FAK/PI3K/AKT pathway: A bioinformatics and experimental study

Zhang S, Sijia Zhang, Yang Y, Yi Yang, Zhang C, Chen Zhang, Xiaoyao Chen, Chen X, Li F, Fawei Li, Jiaoyue Li, Li J, Cheng X, Xi Cheng, Liu X, Xiangtong Liu, Guo Y, Yanan Guo, Zhu Y, Yanning Zhu, Zhai C, Changming Zhai, Xiaona Ma, Ma X
International immunopharmacology · 2025 · vol. 166 , pp. 115563 · doi:10.1016/j.intimp.2025.115563 · PMID:40967048 · W4414273357
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SPP1 was identified as a key modulator of M2 macrophage polarization, promoting endometriosis progression through activation of the FAK/PI3K/AKT pathway.

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Abstract

Endometriosis (EMs) is a gynecological disorder characterized by chronic inflammation and an aberrant immune microenvironment. In this study, we integrated the GSE6364 dataset from the GEO database to identify differentially expressed genes, and applied weighted gene co-expression network analysis (WGCNA) to pinpoint gene modules highly associated with EMs. Cross-referencing with macrophage polarization-related genes, we identified 31 key genes. Machine learning algorithms (LASSO, SVM-RFE, and Random Forest) further narrowed down five core targets: CD44, CLU, FOXO1, MET, and SPP1. Single-cell RNA sequencing revealed that SPP1 is predominantly expressed in M2-like macrophages. Functional assays demonstrated that overexpression of SPP1 promotes macrophage polarization toward the M2 phenotype and significantly enhances the proliferation and migration of human endometrial stromal cells (ihESCs). Mechanistically, SPP1+ M2-like macrophages facilitate lesion growth and invasion via activation of the FAK/PI3K/AKT signaling pathway. Histological and immunofluorescence analyses further confirmed the expression and spatial distribution of these core genes in EMs lesions. Taken together, SPP1 acts as a key regulator in M2 macrophages, playing a crucial role in immune modulation and disease progression in EMs, highlighting its potential as a diagnostic biomarker and therapeutic target.

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Condition tags

endometriosis

MeSH descriptors

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

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Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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