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BackgroundParkinson'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.MethodsPD 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.ResultsMPTP/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. Rescue experiments confirmed that CYLD depletion attenuated ferroptosis, an effect that was rescued by NOX4 overexpression. In MPTP-induced mice, YTHDF2 overexpression alleviated motor deficits (improved locomotion, rotarod performance), and reduced pain hypersensitivity, while mitigating ferroptosis markers and nigral mitochondrial pathology.ConclusionOur study uncovered the YTHDF2/CYLD/NOX4 axis as a novel ferroptosis regulator in PD, revealing a dual epitranscriptomic-posttranslational therapeutic target for neuroprotection.
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