Letter to the editor regarding “Inhibition of Mettl3-mediated m6A RNA modification of HMGCS1 protects retinal ganglion cells from glutamate excitotoxicity-induced ferroptosis in a rat model of glaucoma.”

Dear Editor, We read with great interest the recent article by Wang et al[1] titled “Inhibition of Mettl3-mediated m6A RNA modification of HMGCS1 protects retinal ganglion cells from glutamate excitotoxicity-induced ferroptosis in a rat model of glaucoma.” This study primarily demonstrates that Mettl3-induced m6A methylation of HMGCS1 is recognized by YTHDF2, thereby promoting ferroptosis in retinal ganglion cells (RGCs) in glaucoma. The research primarily utilized two experimental materials: R28 cells and a rat model of glaucoma. Both in vitro and in vivo experiments conclusively proved that inhibiting Mettl3 suppresses ferroptosis in RGCs. We fully endorse the study’s conclusions, which identify a potential therapeutic target for glaucoma treatment. However, the article has limitations that warrant further discussion with the authors. This article has been published in accordance with The TITAN Guidelines, which conducted a transparency review of AI reporting[2]. First, this study employed two experimental materials. Both materials underwent glutamate stimulation at specific concentrations. The authors referenced relevant references[3–5] in Materials section to provide glutamate concentrations for the cell model. However, no literature references were provided regarding glutamate concentrations for the rat model. Moreover, cell experiments were employed to demonstrate glutamate toxicity’s impact on retinal cells. We recommend the authors utilize two glutamate concentrations (e.g. 10 mM, 5 mM) or two time points to broaden the scope of the mechanisms under investigation. Second, the study lacks detailed descriptions in the Materials section regarding the animal model experiments, such as the time interval between modeling completion and drug intervention, the duration of the model after drug intervention, and the dosage and injection timing of lentivirus. We recommend that the authors add relevant descriptions and consider incorporating a flowchart for visual representation. Finally, this study primarily employed the drug, STM2457, to inhibit Mettl3 expression. We observed that interfering with Mettl3 expression in animal models did not affect YTHDF2 expression. This suggests that Mettl3 and YTHDF2 may be two important genes regulating HMGCS1, though their correlation may not be strong. We recommend that the authors further discuss the potential roles of these two genes in the pathogenesis of glaucoma within the Discussion section. In conclusion, we strongly agree with Wang et al’s study[1], which were based on R28 cells and a rat model of glaucoma. Their study demonstrated that inhibiting m6A methylation of HMGCS1 suppresses glutamate toxicity and ferroptosis in RGCs. This represents a potential therapeutic mechanism for glaucoma with significant research value. However, we believe that more detailed descriptions of the article’s methods and results are still warranted.