J Neuropathol Exp Neurol. 2026 Apr 23:nlag027. doi: 10.1093/jnen/nlag027. Online ahead of print.
ABSTRACT
Retinal ganglion cells (RGCs) are particularly vulnerable to damage during the early stages of diabetic retinopathy (DR). Emerging evidence indicates that dysregulated expression of N6-methyladenosine (m6A) methylation regulators contributes to DR pathogenesis. In particular, the m6A reader protein YTHDF3 has been found to be highly expressed in human proliferative DR membranes although its functional role in DR progression remains unclear. In this study, diabetic rat models were established via streptozotocin injection. Subsequently, YTHDF3 expression was knocked down in the retina by intravitreal delivery of AAV-sh-YTHDF3. Additionally, high glucose (HG) conditions were used to induce injury in RGCs in vitro. Our results demonstrated that downregulation of YTHDF3 significantly mitigated HG-induced RGC damage both in vivo and in vitro. YTHDF3 silencing reduced HG-triggered RGC apoptosis by suppressing mitochondrial dysfunction and PINK1-Parkin-mediated excessive mitophagy. Moreover, YTHDF3 functioning as an m6A reader enhanced the translation of PHB2 in an m6A-dependent manner. Notably, PHB2 overexpression effectively counteracted the protective effects of YTHDF3 knockdown, reinstating HG-induced mitochondrial damage and mitophagy. In conclusion, our findings indicate that YTHDF3 exacerbates RGC injury under high glucose conditions by promoting m6A-dependent PHB2 translation, which in turn aggravates mitochondrial damage and PINK1-Parkin-driven mitophagy, thereby contributing to DR progression.
PMID:42024680 | DOI:10.1093/jnen/nlag027