2. Academic Validation
  3. Small-molecule enhancement of METTL3 S-palmitoylation as a therapeutic strategy for osteoarthritis

Small-molecule enhancement of METTL3 S-palmitoylation as a therapeutic strategy for osteoarthritis

  • Cell Rep. 2026 Mar 24;45(3):116993. doi: 10.1016/j.celrep.2026.116993.
Wei Qin 1,  Jiatian Wei 2,  Fuxi Li 3,  Liqiu Wang 4,  Qinkai Zhang 5,  Jian Chen 2,  Peng Lu 2,  Teng Long 2,  Aijun Liu 1,  Jizhao Cao 2,  Yicheng Deng 2,  Huantian Zhang 6,  Dongfeng Chen 7,  Jun Cui 8,  Wei Zhao 9
Affiliations

Affiliations

  • 1 Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 2 Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China.
  • 3 Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
  • 4 MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences of Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
  • 5 Department of Breast and Thyroid Surgery, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, China.
  • 6 Department of Bone and Joint Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China.
  • 7 Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China. Electronic address: [email protected].
  • 8 MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences of Sun Yat-sen University, Guangzhou, Guangdong 510275, China. Electronic address: [email protected].
  • 9 Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China; Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China. Electronic address: [email protected].
PMID: 41719123 DOI: 10.1016/j.celrep.2026.116993
Abstract

METTL3, a key RNA N6-methyladenosine (m6A) methyltransferase, plays essential roles in cell fate regulation and tissue homeostasis, yet therapeutic strategies to enhance its activity remain unexplored. Here, we profile the S-palmitoylation landscape during embryonic stem cell differentiation and observe increased METTL3 S-palmitoylation at cysteine 376 during mesodermal commitment. This modification is catalyzed by ZDHHC24 and reversed by ABHD17A. METTL3 C376S mice exhibit cartilage defects and exacerbated osteoarthritis (OA). Through AI-guided screening, we identify Isoborneol as a small molecule that enhances METTL3 S-palmitoylation by disrupting its interaction with ABHD17A. Isoborneol treatment alleviates joint degeneration and preserves cartilage integrity in OA models. Mechanistically, S-palmitoylation promotes METTL3 condensate formation in proximity to ribosomes, facilitating its cytoplasmic spatial compartmentalization. This condensate state suppresses chaperone-mediated Autophagy, thereby enhancing METTL3 protein stability. Our findings reveal S-palmitoylation as a regulatory mechanism governing METTL3 localization and turnover and establish a pharmacological strategy for restoring METTL3 activity in OA.

Keywords

CP: molecular biology; METTL3 condensate; S-palmitoylation; chaperone-mediated autophagy; isoborneol; osteoarthritis.

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