METTL16 promotes corneal nerve regeneration in diabetic corneal neuropathy.

As a leading ocular disorder caused by diabetes mellitus, diabetic corneal neuropathy (DCN) is characterized by decreased corneal sensation, ocular irritation, delayed corneal wound healing and corneal neuropathic pain. Several researchers including us previously evidenced that DCN is regulated by several transcriptional and/or epigenetic factors. However, the role of N6-methyladenosine (m6A) modification, the most common internal modification in eukaryotic RNAs, in the pathogenesis of DCN remains largely unexplored. In the current work, we aimed to elucidate the pathological role of m6A modification in DCN. Using an m6A epitranscriptomic microarray, we identified differentially m6A-modified mRNAs in DCN. Additionally, we identified a significant decrease in the expression of methyltransferase-Like Protein 16 (METTL16) in trigeminal ganglion (TG) tissues of diabetic mice. Notably, using corneal epithelial nerve injury model and subconjunctival injection of adeno-associated virus, we demonstrated that activation of METTL16 promotes corneal nerve regeneration and accelerates corneal wound healing in DCN mice, suggesting the therapeutic potential of METTL16 in DCN. Moreover, by multi-omics approach, correlation analysis and experimental verification, we identified P4ha1, Pcm1, Ccnd1 and Hsph1 as potential targets of METTL16, revealing the molecular mechanism mediated by METTL16. We also observed a reduction in METTL16 levels in the peripheral blood of diabetic patients, indicating that METTL16 may serve as a potential biomarker for disorders associated with hyperglycemia. In light of these results, aberrant regulation of METTL16 may represent one of the pathogenic mechanisms underlying DCN and could serve as a potential therapeutic target for its treatment.