2. Academic Validation
  3. α-Ketoglutarate protects against cartilage damage via epigenetically driven metabolic reprogramming in osteoarthritis models

α-Ketoglutarate protects against cartilage damage via epigenetically driven metabolic reprogramming in osteoarthritis models

  • J Clin Invest. 2026 Mar 2;136(5):e172380. doi: 10.1172/JCI172380.
Shuaijun Li 1 2,  Jiefeng Huang 1,  Ting Shang 3,  Laiya Lu 4,  Orion R Fan 2 5,  Peisheng Jin 6,  Xin Zou 7,  Zixin Cai 1,  Wuyan Lu 1,  Shuangmeng Jia 1,  Linxiao Li 1,  Ke Fang 1,  Fengting Niu 1,  Jiaojiao Li 1,  Cheng Zhao 2,  Qian Wang 2,  Ruizhu Sun 2,  Si Shi 2,  Feng Yin 4,  Yun Zhang 4,  Yi Eve Sun 2 5 8,  Lei Cui 1 2 9
Affiliations

Affiliations

  • 1 Department of Plastic Surgery, Shanghai Tenth People's Hospital and.
  • 2 Stem Cell Translational Research Center, School of Medicine, Tongji University, Shanghai, China.
  • 3 Department of Plastic Surgery, Beijing Shijitan Hospital affiliated with Capital Medical University, Beijing, China.
  • 4 Department of Joint Surgery and.
  • 5 Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 6 Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
  • 7 Jinshan Hospital Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China.
  • 8 Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology, Shenzhen, Guangdong, China.
  • 9 Department of Plastic Surgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
PMID: 41766657 DOI: 10.1172/JCI172380
Abstract

The link between glutaminolysis and osteoarthritis (OA) has only recently begun to be elucidated. Here, we report the association of obesity- and injury-induced cartilage damage with impaired glutaminolysis in chondrocytes. Defective glutaminolysis triggered the onset and progression of OA, with enhanced catabolism and decreased anabolism. Supplementation of α-ketoglutarate (αKG), a key component in glutaminolysis and an epigenetic factor, effectively protected cartilage against degradation in vivo via a TCA cycle- and HIF-1α-independent manner. Mechanistically, OA pathogenic factors increased H3K27me3 deposition on promoters of key glutaminolysis genes, including Slc1a5 and Gls1, leading to impaired glutaminolysis. Conversely, αKG facilitated Kdm6b-dependent H3K27me3 demethylation of not only glutaminolysis genes to rescue Gln metabolism but also Ube2o to reverse OA. Elevated Ube2o expression led to TRAF6 ubiquitination and subsequent inhibition of NF-κB signaling, thereby reversing the pathological reprogramming of glycolysis and Oxidative Phosphorylation and protecting against cartilage destruction. Collectively, these results demonstrated that OA pathogenic factors impair glutaminolysis through epigenetic regulation, which further exacerbate OA. Moreover, αKG restores metabolic homeostasis and alleviates OA through H3K27me3 demethylation.

Keywords

Cartilage; Inflammation; Metabolism.

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