Knockdown of fat mass and obesity alleviates the ferroptosis in Parkinson's disease through m6A‐NRF2‐dependent manner

Emerging evidence has suggested that N⁶ -methyladenosine (m⁶ A) regulates the pathology of Parkinson's disease (PD). Nevertheless, the function of demethylase fat mass and obesity (FTO) associated pathogenesis is still not fully elucidated. Here, this research findings revealed that m⁶ A-modification was decreased in PD models, meanwhile, the FTO level upregulated in the PD models. Functionally, in N-methyl-4-phenylpyridinium (MPP+) treated SH-SY5Y cells, the ferroptosis significantly upregulated and FTO silencing mitigated the ferroptosis phenotype. Moreover, in silico assays indicated that nuclear factor erythroid 2-related factor-2 (NRF2) acted as the target of FTO, and FTO demethylated the m⁶ A modification from NRF2 mRNA. Furthermore, FTO impaired the NRF2 mRNA stability via m⁶ A-dependent pathway. Thus, our findings illustrated an important role of FTO on PD through m⁶ A-NRF2-ferroptosis manner. Taken together, the study revealed the potential function of FTO on PD nervous system diseases.