SERPINB5 and SPAG6 as candidate correlates of the molecular pathology of idiopathic pulmonary fibrosis: integrated bioinformatics and in vivo evidence
Abstract
ObjectiveThis study aims to elucidate the molecular pathology of idiopathic pulmonary fibrosis (IPF) by identifying key genes associated with extracellular matrix (ECM) organization and remodeling, and immune dysregulation.MethodsDifferentially expressed genes (DEGs) were identified from three Gene Expression Omnibus datasets (GSE110147, GSE21369, GSE24206) using limma and robust rank aggregation (RRA). Functional enrichment and protein-protein interaction network analyses were performed to prioritize hub genes. Diagnostic potential was assessed via receiver operating characteristic (ROC) curves in an independent cohort (GSE32537; 119 patients with IPF and 50 healthy controls), with bootstrap optimism correction and repeated cross-validation. Immune infiltration was quantified using CIBERSORT and cross-validated by single-sample gene set enrichment analysis (ssGSEA). Preliminary validation was performed in a bleomycin-induced murine model using Western blotting, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and immunofluorescence.Results409 robust DEGs were identified, significantly enriched in ECM organization and ciliary structure and motility. CDH2, HYDIN, MMP13, SERPINB5, SERPINF1, and SPAG6 were established as hub genes, demonstrating strong diagnostic performance (individual-gene AUCs ranging from 0.832 to 0.951, combined AUC = 0.981; bootstrap optimism-corrected AUC = 0.971). IPF tissues exhibited altered immune landscapes, characterized by diminished M1 macrophage infiltration. SERPINB5 and SPAG6 exhibited significant negative correlations with M1 macrophage signatures (ρ = −0.41 and −0.46, respectively). In vivo, both genes were significantly upregulated in fibrotic lung tissues and showed qualitative colocalization with macrophage markers. Cross-validation by ssGSEA independently reproduced the diminished M1 macrophage signature and the negative SERPINB5/SPAG6–M1 correlations.ConclusionSERPINB5 and SPAG6 are identified herein as candidate correlates of the molecular pathology of IPF. Their association with ECM remodeling and M1 macrophage polarization is consistent with a functionally relevant role within the fibrotic network. These results provide a foundation for future functional studies aimed at elucidating their precise roles in pulmonary fibrosis.
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BibTeX
@article{li2026serpinb5,
title = {{SERPINB5 and SPAG6 as candidate correlates of the molecular pathology of idiopathic pulmonary fibrosis: integrated bioinformatics and in vivo evidence}},
author = {Siya Li and Peihan Li and Jian Liu and Wenying Zhang and Chenjing Zhu and Cong Wang and Heng Zhang and Qingqing Xia and Huizhe Zhang and Yufeng Zhang},
journal = {Frontiers in Molecular Biosciences},
year = {2026},
month = nov,
doi = {10.3389/fmolb.2026.1906896},
url = {https://www.frontiersin.org/articles/10.3389/fmolb.2026.1906896},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SERPINB5 and SPAG6 as candidate correlates of the molecular pathology of idiopathic pulmonary fibrosis: integrated bioinformatics and in vivo evidence
AU - Siya Li
AU - Peihan Li
AU - Jian Liu
AU - Wenying Zhang
AU - Chenjing Zhu
AU - Cong Wang
AU - Heng Zhang
AU - Qingqing Xia
AU - Huizhe Zhang
AU - Yufeng Zhang
PY - 2026
DA - 2026/11/10
JO - Frontiers in Molecular Biosciences
DO - 10.3389/fmolb.2026.1906896
UR - https://www.frontiersin.org/articles/10.3389/fmolb.2026.1906896
AB - ObjectiveThis study aims to elucidate the molecular pathology of idiopathic pulmonary fibrosis (IPF) by identifying key genes associated with extracellular matrix (ECM) organization and remodeling, and immune dysregulation.MethodsDifferentially expressed genes (DEGs) were identified from three Gene Expression Omnibus datasets (GSE110147, GSE21369, GSE24206) using limma and robust rank aggregation (RRA). Functional enrichment and protein-protein interaction network analyses were performed to prioritize hub genes. Diagnostic potential was assessed via receiver operating characteristic (ROC) curves in an independent cohort (GSE32537; 119 patients with IPF and 50 healthy controls), with bootstrap optimism correction and repeated cross-validation. Immune infiltration was quantified using CIBERSORT and cross-validated by single-sample gene set enrichment analysis (ssGSEA). Preliminary validation was performed in a bleomycin-induced murine model using Western blotting, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and immunofluorescence.Results409 robust DEGs were identified, significantly enriched in ECM organization and ciliary structure and motility. CDH2, HYDIN, MMP13, SERPINB5, SERPINF1, and SPAG6 were established as hub genes, demonstrating strong diagnostic performance (individual-gene AUCs ranging from 0.832 to 0.951, combined AUC = 0.981; bootstrap optimism-corrected AUC = 0.971). IPF tissues exhibited altered immune landscapes, characterized by diminished M1 macrophage infiltration. SERPINB5 and SPAG6 exhibited significant negative correlations with M1 macrophage signatures (ρ = −0.41 and −0.46, respectively). In vivo, both genes were significantly upregulated in fibrotic lung tissues and showed qualitative colocalization with macrophage markers. Cross-validation by ssGSEA independently reproduced the diminished M1 macrophage signature and the negative SERPINB5/SPAG6–M1 correlations.ConclusionSERPINB5 and SPAG6 are identified herein as candidate correlates of the molecular pathology of IPF. Their association with ECM remodeling and M1 macrophage polarization is consistent with a functionally relevant role within the fibrotic network. These results provide a foundation for future functional studies aimed at elucidating their precise roles in pulmonary fibrosis.
SN - 2296-889X
ER -