Engagement of N⁶-methyladenisine methylation of Gng4 mRNA in astrocyte dysfunction regulated by CircHECW2

The N⁶-methyladenosine (m⁶A) modification is the most prevalent modification of eukaryotic mRNAs and plays a crucial role in various physiological processes by regulating the stability or function of target mRNAs. Accumulating evidence has suggested that m⁶A methylation may be involved in the pathological process of major depressive disorder (MDD), a common neuropsychiatric disorder with an unclear aetiology. Here, we found that the levels of the circular RNA HECW2 (circHECW2) were significantly increased in the plasma of both MDD patients and the chronic unpredictable stress (CUS) mouse model. Notably, the downregulation of circHECW2 attenuated astrocyte dysfunction and depression-like behaviors induced by CUS. Furthermore, we demonstrated that the downregulation of circHECW2 increased the expression of the methylase WTAP, leading to an increase in Gng4 expression via m⁶A modifications. Our findings provide functional insight into the correlation between circHECW2 and m⁶A methylation, suggesting that circHECW2 may represent a potential target for MDD treatment.