ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1608378
This article is part of the Research TopicCommunity Series in Crosstalk in Ferroptosis, Immunity & Inflammation: Volume IIView all articles
Single-Cell Transcriptome and Multi-Omics Integration Reveal Ferroptosis-Driven Immune Microenvironment Remodeling in Knee Osteoarthritis
Provisionally accepted
- 1The Second Affiliated Hospital, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, China
- 2The Affiliated Hospital of Fujian University of Traditional Chinese Medicine, fuzhou, China
- 3Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, China
- 4Fujian Normal University, Fuzhou, Fujian Province, China
- 5Affiliated Rehabilitation Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China
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Background: 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.We 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.Results: Twelve 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.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 (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.
Keywords: knee osteoarthritis1, ferroptosis2, Single-cell transcriptomics3, immune microenvironment4, Diagnostic biomarkers5
Received: 08 Apr 2025; Accepted: 10 Jun 2025.
Copyright: © 2025 Wu, liu, Yu, Wang, Li and Zeng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Jian Li, The Second Affiliated Hospital, Fujian University of Traditional Chinese Medicine, Fuzhou, 350003, Fujian Province, China
Weiquan Zeng, Affiliated Rehabilitation Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China
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