Integrative gene ontology-driven analysis of the eutopic endometrium reveals key dysregulated functionomes and pathways in endometriosis

Jyun-Cheng Ke, Chang CM, Chia-Ming Chang, C C Chang, Peng-Hui Wang, Wang PH, Yu-Chi Wang, Wang YC, Y C Wang, Hsieh PL, Ping-Lin Hsieh, Ping‐Lin Hsieh, Kuo‐Min Su
Journal of the Chinese Medical Association : JCMA · 2026 · vol. 89(6) , pp. 415–422 · doi:10.1097/jcma.0000000000001382 · PMID:42037118 · PMC13286419 · W7155895651
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⚙ AI-generated summary by claude@2026-06, 2026-06-13 ⓘ

This study identified widespread immune, metabolic, angiogenic, and extracellular matrix pathway dysregulation in endometriosis eutopic endometrium, highlighting a significant disruption in copper ion homeostasis via a recurrent four-gene signature.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-11 · read from full text ⓘ

This study used an integrative gene ontology–driven functionome analysis of publicly available transcriptomic datasets to characterize dysregulated biological functions in eutopic endometrium from women with endometriosis, comparing 196 patients with 246 healthy controls. Using a modified Differential Rank Conservation approach to generate sample-specific Gene Set Regularity indices across 10,192 GO gene sets, combined with exploratory factor analysis and support vector machine learning, the authors identified widespread dysregulation of immune, metabolic, angiogenic, and extracellular matrix–related pathways, including multiple top dysregulated functionomes linked to copper ion transport. They report a recurrent four-gene copper-regulatory transcriptomic signature (ATP7A, ATP7B, ATOX1, SLC31A1; p<0.05), interpreted as coordinated disruption of copper homeostasis, while noting that causal relationships cannot be established from this comparative design. This paper is centrally about endometriosis—mapping dysregulated copper homeostasis and cuproptosis-related pathways in the eutopic endometrium of people with endometriosis.

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Abstract

BACKGROUND: Endometriosis is a chronic estrogen-dependent inflammatory disorder associated with pelvic pain, infertility, and an increased risk of endometriosis-associated ovarian cancer. Despite extensive research, its molecular mechanisms remain incompletely understood. This study aimed to identify dysregulated biological functions and potential molecular signatures in the eutopic endometrium of women with endometriosis using an integrative functionome-based approach. METHODS: An integrative gene ontology-driven functionome analysis was conducted using publicly available transcriptomic datasets. A modified Differential Rank Conservation algorithm was applied to reconstruct sample-specific Gene Set Regularity (GSR) indices across 10 192 gene ontology (GO)-defined gene sets. Statistical analyses, exploratory factor analysis, and support vector machine (SVM)-based machine learning were used to identify dysregulated functionomes, dysfunctional pathways, and key differentially expressed genes (DEGs). RESULTS: The analysis included 196 patients with endometriosis and 246 healthy controls. Functionome profiling revealed widespread dysregulation of immune, metabolic, angiogenic, and extracellular matrix-related pathways. Among the top 50 dysregulated functionomes, eight were related to copper ion transport and homeostasis. Integrative analysis identified a recurrent four-gene copper-regulatory signature consisting of ATP7A , ATP7B , ATOX1 , and SLC31A1 ( p < 0.05), suggesting coordinated disruption of copper homeostasis in endometriosis. CONCLUSION: Dysregulation of copper ion homeostasis and cuproptosis-related pathways may represent a previously underappreciated molecular feature of endometriosis. Although causal relationships cannot be established from this comparative analysis, the identified copper-regulatory signature provides a reproducible transcriptomic framework for future mechanistic and translational studies.
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Background

Endometriosis is a chronic estrogen-dependent inflammatory disorder associated with pelvic pain, infertility, and an increased risk of endometriosis-associated ovarian cancer. Despite extensive research, its molecular mechanisms remain incompletely understood. This study aimed to identify dysregulated biological functions and potential molecular signatures in the eutopic endometrium of women with endometriosis using an integrative functionome-based approach.

Methods

An integrative gene ontology–driven functionome analysis was conducted using publicly available transcriptomic datasets. A modified Differential Rank Conservation algorithm was applied to reconstruct sample-specific Gene Set Regularity (GSR) indices across 10,192 Gene Ontology (GO)–defined gene sets. Statistical analyses, exploratory factor analysis, and support vector machine (SVM)–based machine learning were used to identify dysregulated functionomes, dysfunctional pathways, and key differentially expressed genes (DEGs).

Results

The analysis included 196 patients with endometriosis and 246 healthy controls. Functionome profiling revealed widespread dysregulation of immune, metabolic, angiogenic, and extracellular matrix–related pathways. Among the top 50 dysregulated functionomes, eight were related to copper ion transport and homeostasis. Integrative analysis identified a recurrent four-gene copper-regulatory signature consisting of ATP7A, ATP7B, ATOX1, and SLC31A1 (p <0.05), suggesting coordinated disruption of copper homeostasis in endometriosis.

Conclusion

Dysregulation of copper ion homeostasis and cuproptosis-related pathways may represent a previously underappreciated molecular feature of endometriosis. Although causal relationships cannot be established from this comparative analysis, the identified copper-regulatory signature provides a reproducible transcriptomic framework for future mechanistic and translational studies.

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Condition tags

endometriosisinfertility

MeSH descriptors

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

Citation neighborhood

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.

References (35)

SciLite annotations

chemicals 50
copper copper copper estrogen copper copper copper estrogen progesterone estrogen estrogen amino acid copper copper copper copper copper copper copper copper copper copper copper copper progesterone estrogen copper oxygen zinc zinc copper copper copper copper copper copper copper copper copper platinum cisplatin platinum copper platinum copper copper copper estrogen copper copper
organisms 7
noordeloos 2009062 noordeloos 2009062 human human human noordeloos 2009062 rodents

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