m6A Demethylase FTO-Mediated Upregulation of BAP1 Induces Neuronal Ferroptosis via the p53/SLC7A11 Axis in the MPP<SUP>+</SUP>/MPTP-Induced Parkinson's Disease Model

作     者：Li, Zhengyu Chen, Xin Xiang, Wenwen Tang, Ting Gan, Li 

作者机构：Nanchang Univ Affiliated Hosp 2 Jiangxi Med Coll Dept Neurol Nanchang 330006 Jiangxi Peoples R China 

出 版 物：《ACS CHEMICAL NEUROSCIENCE》 (ACS Chem. Neurosci.)

年 卷 期：2025年第16卷第3期

页      面：405-416页

核心收录：

基　　金：Jiangxi Provincial Natural Science Foundation [20212BAB206046, 20232BAB206065] Science and Technology Plan of Jiangxi Health Committee National Natural Science Foundation incubation project of the Second Affiliated Hospital of Nanchang University [2021YNFY12007] Youth Fund of the Second Affiliated Hospital of Nanchang University [2019YNQN2011] 

主　　题：BAP1 FTO neuronal ferroptosis p53 Parkinson'sdisease YTHDF2 

摘      要：Background: Parkinson s disease (PD) is a neurodegenerative disorder characterized by the involvement of ferroptosis in its pathological mechanism. In this study, the effects and mechanism of BRCA1-associated protein 1 (BAP1) on neuronal ferroptosis in PD were evaluated. Methods: A PD mouse model was constructed by injecting mice with MPTP. Nissl staining, immunohistochemistry, immunofluorescence, and Prussian blue staining evaluated histopathology and iron distribution. The PD cell model was constructed by subjecting SK-N-SH cells to MPP+. The m6A level of BAP1 was assessed by MeRIP. mRNA levels of BAP1, FTO, IGF2BP1, METTL3, YTHDF2, and SLC7A11 were evaluated utilizing RT-qPCR. Protein levels of BAP1, FTO, IGF2BP1, METTL3, YTHDF2, SLC7A11, and p53 were measured by Western blot. Cell viability was assessed using CCK-8 assay, and TUNEL was used for assessing apoptosis. The levels of MDA, GSH, SOD, and Fe2+ were also measured. The interactions among molecules were verified using RIP assay, dual luciferase reporter assay, and ChIP assay. Results: SK-N-SH cells treated with MPP+ showed a decrease in overall m6A levels of BAP1. FTO facilitated m6A demethylation of BAP1, leading to an increased level of expression of BAP1. m6A-binding protein, YTHDF2 recognized and decayed methylated mRNA of BAP1, leading to the reduced BAP1 stability. The FTO/BAP1 axis promoted MPP+-induced ferroptosis by suppressing SLC7A11. BAP1, in collaboration with p53, reduced the level of expression of SLC7A11. Knocking down BAP1 mitigated ferroptosis in an MPTP mouse model. Conclusion: m6A-mediated modification of BAP1 regulates neuronal ferroptosis by cooperating with p53 to decrease the level of SLC7A11. Thus, BAP1 may be a potential therapeutic target for PD treatment.