{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:26:11Z","timestamp":1791919571558,"version":"4.3.4"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Background<\/jats:title>\n Knee 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.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We analyzed scRNA-seq data (GSE255460,\n n<\/jats:italic>\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 &gt;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.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Twelve chondrocyte clusters were identified, including ferroptosis-active homeostasis chondrocytes (HomC) (\n p<\/jats:italic>\n &lt; 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.,\n SREBF1<\/jats:italic>\n ,\n YY1<\/jats:italic>\n ) driving matrix metalloproteinase activation. A 7-gene diagnostic panel (\n IFT88<\/jats:italic>\n ,\n MIEF2<\/jats:italic>\n ,\n ABCC10<\/jats:italic>\n , etc.) achieved AUC = 1.0 (training) and 0.78 (validation). Immune profiling showed reduced resting mast cells (\n p<\/jats:italic>\n = 0.003) and monocytes (\n p<\/jats:italic>\n = 0.02), with\n ABCC10<\/jats:italic>\n correlating negatively with CD8+ T cells (\n r<\/jats:italic>\n = -0.65) and M1 macrophages. GSEA\/GSVA implicated HIF-1, NF-\u03baB, and oxidative phosphorylation pathways in KOA progression. Pseudotime analysis revealed fibrotic transitions (\n COL1A1<\/jats:italic>\n \u2191,\n TNC<\/jats:italic>\n \u2191) in late-stage KOA cells.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n This 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 (\n SREBF1\/YY1<\/jats:italic>\n ) 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.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1608378","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T06:59:50Z","timestamp":1750834790000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Single-cell transcriptome and multi-omics integration reveal ferroptosis-driven immune microenvironment remodeling in knee 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