Small-molecule enhancement of METTL3 S-palmitoylation as a therapeutic strategy for osteoarthritis - PubMed
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- #S-palmitoylation
- #METTL3
- #osteoarthritis
- METTL3 is a key RNA N6-methyladenosine (m6A) methyltransferase involved in cell fate regulation and tissue homeostasis.
- Increased METTL3 S-palmitoylation at cysteine 376 occurs during mesodermal commitment, catalyzed by ZDHHC24 and reversed by ABHD17A.
- METTL3 C376S mice show cartilage defects and exacerbated osteoarthritis (OA).
- Isoborneol, identified through AI-guided screening, enhances METTL3 S-palmitoylation by disrupting its interaction with ABHD17A.
- Isoborneol treatment alleviates joint degeneration and preserves cartilage integrity in OA models.
- S-palmitoylation promotes METTL3 condensate formation near ribosomes, facilitating cytoplasmic spatial compartmentalization.
- This condensate state suppresses chaperone-mediated autophagy, enhancing METTL3 protein stability.
- The study reveals S-palmitoylation as a regulatory mechanism for METTL3 localization and turnover, offering a pharmacological strategy for OA treatment.