Single-cell transcriptome and multi-omics integration reveal ferroptosis-driven immune microenvironment remodeling in knee osteoarthritis
BackgroundKnee osteoarthritis (KOA) is a chronic inflammatory joint disorder marked by cartilage degradation and immune microenvironment dysregulation. While transcriptomic studies have identified key pathways in KOA, the interplay between ferroptosis (an iron-dependent cell death mechanism) and imm...
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Frontiers Media S.A.
2025-06-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1608378/full |
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| author | Yushun Wu Jing Liu Wenying Yu Xiaoding Wang Jian Li Weiquan Zeng |
| author_facet | Yushun Wu Jing Liu Wenying Yu Xiaoding Wang Jian Li Weiquan Zeng |
| author_sort | Yushun Wu |
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| description | BackgroundKnee osteoarthritis (KOA) is a chronic inflammatory joint disorder marked by cartilage degradation and immune microenvironment dysregulation. While transcriptomic studies have identified key pathways in KOA, the interplay between ferroptosis (an iron-dependent cell death mechanism) and immune dysfunction at single-cell resolution remains unexplored. This study integrates single-cell and bulk transcriptomics to dissect ferroptosis-driven immune remodeling and identify diagnostic biomarkers in KOA.MethodsWe analyzed scRNA-seq data (GSE255460, n = 11) and bulk RNA-seq cohorts (GSE114007: 20 KOA/18 controls; GSE246425: 8 KOA/4 controls). Single-cell data were processed via Seurat (QC: mitochondrial genes >3 MAD; normalization: LogNormalize; batch correction: Harmony) and annotated using CellMarker/PanglaoDB. CellChat decoded intercellular communication, SCENIC reconstructed transcriptional networks, and Monocle2 for pseudotime trajectory mapping. Immune infiltration (CIBERSORT) and a LASSO-SVM diagnostic model were validated by ROC curves. Functional enrichment (GSEA/GSVA) and immunometabolic profiling were performed.ResultsTwelve chondrocyte clusters were identified, including ferroptosis-active homeostasis chondrocytes (HomC) (p < 0.01), which exhibited 491 DEGs linked to lipid peroxidation. HomC orchestrated synovitis via FGF signaling (ligand-receptor pairs: FGF1-FGFR1), amplifying ECM degradation and inflammatory cascades (CellChat). SCENIC revealed 10 HomC-specific regulons (e.g., SREBF1, YY1) driving matrix metalloproteinase activation. A 7-gene diagnostic panel (IFT88, MIEF2, ABCC10, etc.) achieved AUC = 1.0 (training) and 0.78 (validation). Immune profiling showed reduced resting mast cells (p = 0.003) and monocytes (p = 0.02), with ABCC10 correlating negatively with CD8+ T cells (r = -0.65) and M1 macrophages. GSEA/GSVA implicated HIF-1, NF-κB, and oxidative phosphorylation pathways in KOA progression. Pseudotime analysis revealed fibrotic transitions (COL1A1↑, TNC↑) in late-stage KOA cells.ConclusionThis study establishes ferroptosis as one of the key drivers immune-metabolic dysfunction in KOA, with HomC acting as a hub for FGF-mediated synovitis and ECM remodeling. The diagnostic model and regulon network (SREBF1/YY1) offer translational tools for early detection, while impaired mast cell homeostasis highlights novel immunotherapeutic targets. Our findings bridge ferroptosis, immune dysregulation, and metabolic stress, advancing precision strategies for KOA management. |
| format | Article |
| id | doaj-art-52bf0019174b4b4ca7d239cb0e8f551c |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-06-01 |
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| series | Frontiers in Immunology |
| spelling | doaj-art-52bf0019174b4b4ca7d239cb0e8f551c2025-08-20T03:23:50ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.16083781608378Single-cell transcriptome and multi-omics integration reveal ferroptosis-driven immune microenvironment remodeling in knee osteoarthritisYushun Wu0Jing Liu1Wenying Yu2Xiaoding Wang3Jian Li4Weiquan Zeng5Department of Sports Medicine, The Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaDepartment of Pain Management, The Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaThe First Clinical Medical College, Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaCollege of Computer and Network Space Security, Fujian Normal University, Fuzhou, ChinaDepartment of Sports Medicine, The Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaDepartment of Orthopedics, The Rehabilitation Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, ChinaBackgroundKnee osteoarthritis (KOA) is a chronic inflammatory joint disorder marked by cartilage degradation and immune microenvironment dysregulation. While transcriptomic studies have identified key pathways in KOA, the interplay between ferroptosis (an iron-dependent cell death mechanism) and immune dysfunction at single-cell resolution remains unexplored. This study integrates single-cell and bulk transcriptomics to dissect ferroptosis-driven immune remodeling and identify diagnostic biomarkers in KOA.MethodsWe analyzed scRNA-seq data (GSE255460, n = 11) and bulk RNA-seq cohorts (GSE114007: 20 KOA/18 controls; GSE246425: 8 KOA/4 controls). Single-cell data were processed via Seurat (QC: mitochondrial genes >3 MAD; normalization: LogNormalize; batch correction: Harmony) and annotated using CellMarker/PanglaoDB. CellChat decoded intercellular communication, SCENIC reconstructed transcriptional networks, and Monocle2 for pseudotime trajectory mapping. Immune infiltration (CIBERSORT) and a LASSO-SVM diagnostic model were validated by ROC curves. Functional enrichment (GSEA/GSVA) and immunometabolic profiling were performed.ResultsTwelve chondrocyte clusters were identified, including ferroptosis-active homeostasis chondrocytes (HomC) (p < 0.01), which exhibited 491 DEGs linked to lipid peroxidation. HomC orchestrated synovitis via FGF signaling (ligand-receptor pairs: FGF1-FGFR1), amplifying ECM degradation and inflammatory cascades (CellChat). SCENIC revealed 10 HomC-specific regulons (e.g., SREBF1, YY1) driving matrix metalloproteinase activation. A 7-gene diagnostic panel (IFT88, MIEF2, ABCC10, etc.) achieved AUC = 1.0 (training) and 0.78 (validation). Immune profiling showed reduced resting mast cells (p = 0.003) and monocytes (p = 0.02), with ABCC10 correlating negatively with CD8+ T cells (r = -0.65) and M1 macrophages. GSEA/GSVA implicated HIF-1, NF-κB, and oxidative phosphorylation pathways in KOA progression. Pseudotime analysis revealed fibrotic transitions (COL1A1↑, TNC↑) in late-stage KOA cells.ConclusionThis study establishes ferroptosis as one of the key drivers immune-metabolic dysfunction in KOA, with HomC acting as a hub for FGF-mediated synovitis and ECM remodeling. The diagnostic model and regulon network (SREBF1/YY1) offer translational tools for early detection, while impaired mast cell homeostasis highlights novel immunotherapeutic targets. Our findings bridge ferroptosis, immune dysregulation, and metabolic stress, advancing precision strategies for KOA management.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1608378/fullknee osteoarthritisferroptosissingle-cell transcriptomicsimmune microenvironmentdiagnostic biomarkers |
| spellingShingle | Yushun Wu Jing Liu Wenying Yu Xiaoding Wang Jian Li Weiquan Zeng Single-cell transcriptome and multi-omics integration reveal ferroptosis-driven immune microenvironment remodeling in knee osteoarthritis Frontiers in Immunology knee osteoarthritis ferroptosis single-cell transcriptomics immune microenvironment diagnostic biomarkers |
| title | Single-cell transcriptome and multi-omics integration reveal ferroptosis-driven immune microenvironment remodeling in knee osteoarthritis |
| title_full | Single-cell transcriptome and multi-omics integration reveal ferroptosis-driven immune microenvironment remodeling in knee osteoarthritis |
| title_fullStr | Single-cell transcriptome and multi-omics integration reveal ferroptosis-driven immune microenvironment remodeling in knee osteoarthritis |
| title_full_unstemmed | Single-cell transcriptome and multi-omics integration reveal ferroptosis-driven immune microenvironment remodeling in knee osteoarthritis |
| title_short | Single-cell transcriptome and multi-omics integration reveal ferroptosis-driven immune microenvironment remodeling in knee osteoarthritis |
| title_sort | single cell transcriptome and multi omics integration reveal ferroptosis driven immune microenvironment remodeling in knee osteoarthritis |
| topic | knee osteoarthritis ferroptosis single-cell transcriptomics immune microenvironment diagnostic biomarkers |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1608378/full |
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