Yu, C.; Xu, C.; Zhang, J.; Wang, M.; Qian, M.; Liu, B.

YTH domain-containing family (YTHDF1/2/3) recognizes m6A modified mRNAs and regulates their stability, translation and function. We found loss of Ythdf3 in mice caused cardiac hypotrophy, myopathy, and intellectual abnormalities, resembling the clinical features of a rare inherited X-linked disorder Danon disease (DD). Mechanistically, this was attributable to the compromised mRNA decay of sex-determining region Y (SRY)-box 9 (Sox9), mediated by YTHDF3 m6A reader function. Targeted therapy with AAV-shRNA against Sox9 ameliorated fibrosis, increased neuron number, and significantly improved heart and brain function in Ythdf3-/- mice. Our data reveal that loss of murine Ythdf3 recapitulates systemic DD-like features, attributable to impaired Sox9 decay, and highlight a novel therapeutic target for DD.