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Targeting macrophage polarization has emerged as a promising avenue for OA treatment. This study identified skatole through high-throughput screening as an efficient modulator of macrophage polarization. In\u00a0vivo experiments demonstrated that skatole administration markedly reduced synovitis and cartilage damage in both destabilization of medial meniscus (DMM)-induced OA mice and monosodium iodoacetate (MIA)-induced OA rats. Mechanistically, skatole activated signal transducer and activator of transcription 6 (Stat6) signaling, promoting M2 macrophage polarization, while inhibiting nuclear factor-\u03baB (NF\u03baB) and mitogen-activated protein kinase (MAPK) signaling pathways to suppress M1 polarization. RNA-sequencing analysis, targeted metabolomics, and mitochondrial stress tests further revealed that skatole treatment shifted macrophages toward oxidative phosphorylation for energy production. Additionally, it up-regulated genes associated with glutathione metabolism and reactive oxygen species (ROS) pathways, reducing intracellular ROS production. The CUT&amp;Tag assay results indicated that the downstream transcription factor p65 of NF\u03baB can directly bind to gene loci related to inflammation, oxidative phosphorylation, and glutathione metabolism, thereby modulating gene expression. This regulatory process is inhibited by skatole. At the chondrocyte level, conditional medium from skatole-treated M1 macrophages balanced anabolism and catabolism in mouse chondrocytes and inhibited apoptosis. In IL1\u03b2-treated chondrocytes, skatole suppressed inflammation and catabolism without affecting apoptosis or anabolism. Overall, skatole maintains immune microenvironment homeostasis by modulating macrophage polarization in joints and preserves cartilage function by balancing chondrocyte anabolism and catabolism, effectively alleviating OA. These findings suggest skatole\u2019s potential as a DMOAD.<\/jats:p>","DOI":"10.34133\/research.0604","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T09:09:21Z","timestamp":1737364161000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":19,"title":["Skatole Alleviates Osteoarthritis by Reprogramming Macrophage Polarization and Protecting Chondrocytes"],"prefix":"10.34133","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7152-1565","authenticated-orcid":false,"given":"Weiyun","family":"Wang","sequence":"first","affiliation":[{"name":"Institutes of Health Central Plain, Clinical Medical Center of Tissue Engineering and Regeneration, \rXinxiang Medical University, Xinxiang 453003, China."},{"name":"The First Affiliated Hospital, \rXinxiang Medical University, Xinxiang 453199, 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