Inhibition of YTHDF2-mediated CYLD mRNA degradation promotes neuronal ferroptosis and pain in Parkinson's disease through NOX4 deubiquitination

作者：Fei Wang, Shu-Wei Bai, Yuanmei Pan, Zhongjiao Lu, Xianguo Jiang · 发表于：Cell Biology and Toxicology · 年份：2026 · DOI：10.1007/s10565-026-10204-0 · 研究领域：Medicine

Parkinson’s disease (PD) is featured by progressive neurodegeneration linked to iron-dependent ferroptosis, yet the functions of m6A RNA-binding proteins and deubiquitinating enzymes in this process remain poorly understood. This work investigates the functional interplay between the m6A reader YTHDF2 and deubiquitinase CYLD in PD-associated ferroptosis and delineates their downstream molecular mechanisms. PD models were established using MPTP-treated C57BL/6 mice and MPP+-exposed SH-SY5Y neuroblastoma cells. Behavioral assessments (open field, rotarod, and pole tests) and pain sensitivity assays (mechanical allodynia, thermal hyperalgesia) were performed. Molecular analyses included qRT-PCR, Western blot, RNA immunoprecipitation (RIP), co-immunoprecipitation (Co-IP), and ubiquitination assays. Ferroptosis markers (Fe2+, ROS, MDA, and GSH) and key regulators (ACSL4, GPX4, SLC7A11, and FTL) were quantified. Gain- and loss-of-function experiments for YTHDF2, CYLD, and NOX4 were conducted to validate regulatory relationships. MPTP/MPP+ treatment downregulated YTHDF2 and upregulated CYLD, exacerbating ferroptosis, as evidenced by mitochondrial damage, elevated Fe2+/ROS/MDA, reduced GSH, and altered level of ferroptosis-associated proteins (ACSL4 increased, GPX4/SLC7A11/FTL decreased). YTHDF2 overexpression suppressed ferroptosis, at least in part, by recognizing m6A-modified CYLD mRNA and promoting its degradation. Moreover, CYLD stabilized NOX4 by inhibiting its ubiquitination. ...