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

Author

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  • Zixuan Mei

    (Zhejiang University School of Medicine
    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province)

  • Kamuran Yilamu

    (Zhejiang University School of Medicine
    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province)

  • Weiyu Ni

    (Zhejiang University School of Medicine
    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province)

  • Panyang Shen

    (Zhejiang University School of Medicine
    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province)

  • Nan Pan

    (Zhejiang University School of Medicine
    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province)

  • Huasen Chen

    (Zhejiang University School of Medicine
    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province)

  • Yingfeng Su

    (Zhejiang University School of Medicine
    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province)

  • 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
    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province)

  • Shunwu Fan

    (Zhejiang University School of Medicine
    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province)

  • Haitao Zhang

    (Zhejiang University School of Medicine
    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province)

  • Shuying Shen

    (Zhejiang University School of Medicine
    Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province)

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.

Suggested Citation

  • 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 & Shuying S, 2025. "Chondrocyte fatty acid oxidation drives osteoarthritis via SOX9 degradation and epigenetic regulation," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60037-4
    DOI: 10.1038/s41467-025-60037-4
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    References listed on IDEAS

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    3. Wan-Su Choi & Gyuseok Lee & Won-Hyun Song & Jeong-Tae Koh & Jiye Yang & Ji-Sun Kwak & Hyo-Eun Kim & Seul Ki Kim & Young-Ok Son & Hojung Nam & Iljung Jin & Zee-Yong Park & Jiyeon Kim & In Young Park & , 2019. "The CH25H–CYP7B1–RORα axis of cholesterol metabolism regulates osteoarthritis," Nature, Nature, vol. 566(7743), pages 254-258, February.
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