TGF-β1-induced m6A modifications accelerate onset of nuclear cataract in high myopia by modulating the PCP pathway

High myopia is an important cause of visual impairment worldwide, characterized by early-onset nuclear cataracts, whose underlying mechanisms remain largely unexplained. Here, we identify conspicuously polarized and compacted lens fiber alignment, along with a simultaneous rise in N6-methyladenosine (m6A) modifications in patients with highly myopic cataracts (HMC), which is confirmed to be induced by elevated transforming growth factor-β1 (TGF-β1) in lens. Mechanistically, methyltransferase METTL3 and m6A reader insulin-like growth factor 2 mRNA binding protein 3 synergistically enhance planar cell polarity (PCP) signaling by affecting mRNA stability of dishevelled 2. This, in turn, alters proliferation, migration, and polarity formation of human lens epithelial cells. Moreover, Mettl3 conditional knockdown in mice leads to disrupted lens fiber arrangement and alleviates TGF-β1-induced increase in lens nuclear density. Collectively, these findings highlight the significance of m6A-modified PCP pathway in regulating postnatal lens fiber organization, which may hold great promise as a therapeutic target for HMC.