2. Academic Validation
  3. Selective clearance of senescent chondrocytes in osteoarthritis by targeting EAAT1 to induce ferroptosis

Selective clearance of senescent chondrocytes in osteoarthritis by targeting EAAT1 to induce ferroptosis

  • Antioxid Redox Signal. 2023 Jan 5. doi: 10.1089/ars.2022.0141.
Zi Wen 1,  Guang Xia 2,  Chi Liang 3,  Xinxing Wang 4,  Junjie Huang 5 6,  Lina Zhang 7,  Dongyong Shan 8,  Song Wu 9,  Xu Cao 5 10
Affiliations

Affiliations

  • 1 Central South University Third Xiangya Hospital, 504354, Department of Orthopedics, Changsha, Hunan, China; [email protected].
  • 2 Central South University Third Xiangya Hospital, 504354, Department of Orthopedics, Changsha, Hunan, China; [email protected].
  • 3 Central South University Third Xiangya Hospital, 504354, Department of Orthopedics, 138 Tongzipo Road, Changsha, Hunan, China, Changsha, Hunan, China, 410013; [email protected].
  • 4 Central South University Third Xiangya Hospital, 504354, Department of Orthopedics, Changsha, Hunan, China; [email protected].
  • 5 Central South University Third Xiangya Hospital, 504354, Department of Orthopedics, Changsha, Hunan, China.
  • 6 Institute of Basic Medicine and Cancer Chinese Academy of Sciences, 631027, Hangzhou, Zhejiang, China; [email protected].
  • 7 Central South University Third Xiangya Hospital, 504354, Department of Orthopedics, Changsha, Hunan, China; [email protected].
  • 8 Central South University Third Xiangya Hospital, 504354, Department of Oncology, Changsha, Hunan, China; [email protected].
  • 9 Central South University Third Xiangya Hospital, 504354, Department of Orthopedics, Changsha, Hunan, China; [email protected].
  • 10 Institute of Basic Medicine and Cancer Chinese Academy of Sciences, 631027, Hangzhou, Zhejiang, China; [email protected].
PMID: 36601724 DOI: 10.1089/ars.2022.0141
Abstract

Aims: This study aimed to explore the mechanism of Ferroptosis (an iron-dependent form of nonapoptotic cell death) resistance in senescent chondrocytes.

Results: In this study, by utilizing metabolomics and single-cell RNA sequencing, we found that hyperactivation of Ferroptosis metabolism was one of the most prominent metabolic features in Senescent chondrocytes (SenChos). Interestingly, however, SenChos were able to survive in this state and were resistant to Ferroptosis induced cell death. Next, we elucidated that this survival mechanism of SenChos could be primarily attributed to overexpression of the membrane protein excitatory amino acid transporter protein 1 (EAAT1), which can increase intracellular glutamate levels and activate the glutathione system to counteract Ferroptosis. In addition, UCPH-101 (a specific inhibitor of EAAT1) and siRNA-EAAT1 were able to substantially increase the sensitivity of SenChos to Ferroptosis and to induce cell death, with no apparent effects on the normal cells. Administration of intra-articular injection of UCPH-101, caused inhibition of EAAT1 selectively, cleared SenChos from cartilage, improved the cartilage homeostasis and significantly delayed the progression of OA.

Innovation: This work supports a relevant role for EAAT1 in Ferroptosis resistance mechanism for SenChos, revealing a potential OA therapeutic target.

Conclusions: EAAT1-glutamate-GPX4 anti-ferroptosis axis is a key survival mechanism for SenChos and EAAT1 is an effective and specific target for anti-senescence therapy in OA.

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