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ORIGINAL RESEARCH ARTICLE

Transcriptomic analysis reveals inflammatory and metabolic dysregulation in unexplained female infertility

Ritika Patial1 ,  Sonalika Ray2 ,  Kashmir Singh3 ,  Ranbir C. Sobti3*
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1 Centre for Systems Biology and Bioinformatics, Faculty of Science, Panjab University, Chandigarh, Chandigarh, India
2 Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, United States of America
3 Department of Biotechnology, Faculty of Science, Panjab University, Chandigarh, Chandigarh, India
IMO, 026100010 https://doi.org/10.36922/IMO026100010
Received: 3 March 2026 | Revised: 22 June 2026 | Accepted: 6 August 2026 | Published online: 21 August 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Infertility affects the majority of women, and many cases have no clear cause. Endometrial abnormalities are suspected contributors, but the molecular changes behind them remain poorly mapped. We analyzed endometrial tissue transcriptomes from the NCBI GEO dataset GSE92324 to identify differences between women with implantation failure and fertile controls. We performed principal component analysis to assess sample variance and performed differential gene expression analysis with DESeq2. The analysis highlighted 168 significant genes (adjusted p < 0.05, |log2FC| > 2), of which 47 were upregulated and 121 were downregulated. Eleven of these were reproduced in an independent cohort (GSE111974) with fully concordant direction (overlap above chance, hypergeometric p = 1.3e−16): CAPN6, CHST4, CLDN22, DUOXA1, ENPP3, PKHD1L1, SCGB1D4, SLC39A14, SLC7A4, TRPM6, and WNK4. These reproducible genes mapped to epithelial ion transport (WNK4, TRPM6, SLC7A4, SLC39A14, ENPP3), tight junction and barrier function (CLDN22, SCGB1D4), and mitochondrial dysfunction (CAPN6), the same pathways that emerged as the most strongly inhibited across the analysis. Functional enrichment pointed to immune-inflammatory pathways, lipid metabolism, and steroid biosynthesis. Ingenuity Pathway Analysis showed increased innate immune responses, altered lipid metabolism, and inhibited mitochondrial function. Upstream regulator analysis identified PTEN, PRKAA1, HDAC4, IL10RA, and RAD51, which regulate metabolic and anti-inflammatory signaling. Weighted gene co-expression network analysis identified a turquoise module with a strong negative correlation with the trait of interest (correlation = −0.84, p < 0.0001), pointing to C7orf50, a cholesterol-metabolism gene not previously tied to infertility, as a candidate worth following up. Five further genes, C1orf106 (INAVA), C15orf59, LINC00461, C15orf48 (NMES1), and C10orf99 (GPR15LG), had no prior reported link to infertility. Together, these findings map the genes, co-expression modules, and pathways disrupted in unexplained female infertility and nominate a reproducible set of ion-transport and barrier genes as candidate markers.

Keywords
Unexplained female infertility
Endometrial transcriptomics
Weighted gene co-expression network analysis
Ingenuity Pathway Analysis
Ion transport
Funding
None.
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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