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

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.