Osteoarthritis (OA) is the most prevalent joint disease, yet effective disease-modifying OA drugs (DMOADs) remain elusive. 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 vivo 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-κB (NFκB) 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&Tag assay results indicated that the downstream transcription factor p65 of NFκB 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 IL1β-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’s potential as a DMOAD.

人体所有细胞类型都由合子发育而来, 从合子到谱系定型, 再到特化细胞类群的发育过程曾被认为是不可逆的“单向道”; 直到20世纪中叶, 细胞核移植技术的建立与发展使得体细胞命运的逆转成为可能, 并提示发育时钟可以被逆转[1]. 2006年, 日本生物学家Shinya Yamanaka通过转入四个外源转录因子Oct4、Sox2、Klf4和c-Myc (OSKM), 成功将小鼠胚胎/成体成纤维细胞重编程为多能干细胞, 称为诱导多能干细胞(Induced-pluripotent stem cells, iPSCs)[2]. iPSCs具有胚胎干细胞(Embryonic stem cells, ESCs)的形态和生长特性, 可表达ESCs的标志基因, 并且在体内外都表现出三胚层分化潜能. 重编程技术开启了诱导干细胞研究热潮, 极大地推进了再生医学领域的发展, 点燃了人们“返老还童”的梦想. 体内实验显示, 短期间歇性的表达OSKM因子可使衰老小鼠恢复更年轻的表观遗传标记模式[3]. 进一步去掉肿瘤相关的风险因子c-Myc, 将OSK递送到视网膜神经节细胞中, 可成功逆转和恢复青光眼小鼠模型和老年小鼠的视力丧失[4]. 这些结果清楚地表明, 哺乳动物的组织可以通过体内表观重塑回到更年轻的状态.