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
  • 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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