Chondrocyte fatty acid oxidation drives osteoarthritis via SOX9 degradation and epigenetic regulation

Zixuan Mei, Kamuran Yilamu, Weiyu Ni, Panyang Shen, Nan Pan, Huasen Chen, Yingfeng Su, Lei Guo, Qunan Sun, Zhaomei Li, Dongdong Huang, Xiangqian Fang, Shunwu Fan (), Haitao Zhang () and Shuying Shen ()
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Zixuan Mei: Zhejiang University School of Medicine
Kamuran Yilamu: Zhejiang University School of Medicine
Weiyu Ni: Zhejiang University School of Medicine
Panyang Shen: Zhejiang University School of Medicine
Nan Pan: Zhejiang University School of Medicine
Huasen Chen: Zhejiang University School of Medicine
Yingfeng Su: Zhejiang University School of Medicine
Lei Guo: Pooling Institute of Translational Medicine
Qunan Sun: Zhejiang University School of Medicine
Zhaomei Li: Xiaoshan Geriatric Hospital
Dongdong Huang: Pooling Institute of Translational Medicine
Xiangqian Fang: Zhejiang University School of Medicine
Shunwu Fan: Zhejiang University School of Medicine
Haitao Zhang: Zhejiang University School of Medicine
Shuying Shen: Zhejiang University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract Osteoarthritis is the most prevalent age-related degenerative joint disease and is closely linked to obesity. However, the underlying mechanisms remain unclear. Here we show that altered lipid metabolism in chondrocytes, particularly enhanced fatty acid oxidation (FAO), contributes to osteoarthritis progression. Excessive FAO causes acetyl-CoA accumulation, thereby altering protein-acetylation profiles, where the core FAO enzyme HADHA is hyperacetylated and activated, reciprocally boosting FAO activity and exacerbating OA progression. Mechanistically, elevated FAO reduces AMPK activity, impairs SOX9 phosphorylation, and ultimately promotes its ubiquitination-mediated degradation. Additionally, acetyl-CoA orchestrates epigenetic modulation, affecting multiple cellular processes critical for osteoarthritis pathogenesis, including the transcriptional activation of MMP13 and ADAMTS7. Cartilage-targeted delivery of trimetazidine, an FAO inhibitor and AMPK activator, demonstrates superior efficacy in a mouse model of metabolism-associated post-traumatic osteoarthritis. These findings suggest that targeting chondrocyte-lipid metabolism may offer new therapeutic strategies for osteoarthritis.

Date: 2025
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DOI: 10.1038/s41467-025-60037-4

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