LOXL1, THY1, and TYMS define an annotation-derived hemoglobin-associated immunotranscriptomic signature in osteoarthritis cartilage.

Authors

Xin Zhang, Zhaochen Ye, Zheng Qin, Yizhe Li, Zhilong Jing, Dawei Yang

Published in

Frontiers in immunology. Volume 17. Pages 1823558. Epub Jul 09, 2026.

Abstract

Osteoarthritis (OA) is increasingly recognized as a whole-joint disease involving cartilage degeneration, synovial inflammation, subchondral bone remodeling, and immune-associated inflammatory signaling. Non-erythroid hemoglobin (Hb)-associated transcriptional programs have recently been implicated in chondrocyte hypoxic adaptation, but their relationship with immune-associated transcriptomic remodeling in OA cartilage remains unclear. This study aimed to identify annotation-derived Hb-associated transcriptomic biomarkers in OA cartilage and to characterize their associations with inferred immune-related transcriptomic features.
Human cartilage transcriptomic datasets were integrated from Gene Expression Omnibus (GEO) to construct a harmonized training cohort, with independent datasets used for external validation. After batch-effect correction, OA differentially expressed genes were intersected with a GeneCards-derived Hb-associated annotation gene set. Weighted gene co-expression network analysis, together with the least absolute shrinkage and selection operator and other complementary machine-learning approaches, was applied to identify hub Hb-associated OA genes. A multivariable logistic-regression nomogram was constructed and evaluated by receiver operating characteristic analysis across cohorts. Immune pathway activity and immune-cell-associated transcriptomic signatures were inferred using GSVA, CIBERSORT, ssGSEA, and correlation analyses. Experimental validation was performed using qRT-PCR in an interleukin-1β-stimulated inflammatory chondrocyte model.
Three Hb-associated hub genes-LOXL1, THY1, and TYMS-were identified through integrative transcriptomic analysis and consistently upregulated in OA cartilage across training and independent validation cohorts. Immune profiling suggested an immune-activated transcriptomic state in OA cartilage, characterized by increased macrophage-associated signals, reduced resting NK and CD4 memory T cells, elevated activated immune cell signatures, and enhanced antigen presentation-related and immune regulation-related functions. Expression of these Hb-associated hub genes showed strong positive correlations with macrophage- and activated T-cell-related signatures and antigen presentation-associated immune functions. A nomogram based on the three genes demonstrated high discriminative performance across cohorts, with an AUC of 0.974 in the training cohort. qRT-PCR in an IL-1β-stimulated C28/I2 chondrocyte model supported the inflammatory inducibility of LOXL1, THY1, and TYMS.
This study identifies LOXL1, THY1, and TYMS as reproducible annotation-derived Hb-associated tissue-level transcriptomic biomarkers in OA cartilage. Their expression is associated with macrophage- and activated T-cell-related transcriptomic signatures, providing an immunotranscriptomic link between annotation-derived Hb-associated gene programs and immune remodeling in OA.

PMID:
42495609
Bibliographic data and abstract were imported from PubMed on 24 Jul 2026.

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