Methyltransferase-like enzyme 14 exacerbates retinal ganglion cell damage and diabetic retinopathy through N6-methyladenosine-dependent upregulation of pleckstrin homology domain and leucine rich repeat protein phosphatase 2.

N6-methyladenosine (m6A) modification of pleckstrin homology domain and leucine rich repeat protein phosphatase 2 (PHLPP2), mediated by methyltransferase-like enzyme 14 (METTL14), plays a critical role in regulating PHLPP2 expression across various pathological conditions. This study aims to ascertain whether METTL14 influences m6A methylation of PHLPP2 in diabetic retinopathy (DR) and to delineate the precise function of the METTL14/PHLPP2 axis in disease progression. METTL14 levels were observed to be elevated in retinas of DR rats and in HG-stimulated RGCs, coinciding with an increase in PHLPP2 m6A modification. Knockdown of METTL14 resulted in significant reductions in PHLPP2 expression and its m6A modification. Silencing METTL14 mitigated HG-induced damage in RGCs, which was linked to the inhibition of apoptosis, oxidative stress and inflammation. This protective effect could be negated through the restoration of PHLPP2. METTL14 knockdown modulated the AKT/GSK-3β/Nrf2 signal cascade through PHLPP2. Silencing METTL14 resulted in the downregulation of METTL14 and PHLPP2 in the retinas of DR rats, ameliorated visual function impairment and reduced the pathological alterations. These protective effects of METTL14 silencing against DR were also weakened when PHLPP2 was restored. Overall, these results suggest that suppressing METTL14 improves HG-induced damage in RGCs and protects against DR by downregulating PHLPP2 through m6A modification.