MDM2 in the signaling pathways related to neurological diseases

作者：Caizhen Shi, Yajuan Xue, Jiawen Li, Danni Hui, Bingbing Wang, Shenghao Qian, Dan Li, Yanjie Guo, Yan Fan, Juan Shen, Yanling Yang, Kunpeng Jia, Lin Zhao · 发表于：Neurobiology of Disease · 年份：2025 · DOI：10.1016/j.nbd.2025.107200 · 被引用次数：3 · 研究领域：Cancer-related Molecular Pathways、Autophagy in Disease and Therapy、Microtubule and mitosis dynamics

Mouse double minute 2 homolog (MDM2) is a key negative regulator of the p53 pathway, functioning through its E3 ubiquitin ligase activity to control cell-cycle progression, DNA damage response, and apoptosis. Recent findings reveal that MDM2 also plays multifaceted roles in the central nervous system (CNS), extending beyond its canonical oncogenic functions. Increasingly, MDM2 has been implicated in the pathogenesis and progression of neurodegenerative diseases, brain injury, neuroinflammation, and cognitive dysfunction.This review integrates current advances on the non-canonical roles of MDM2 in CNS disorders, focusing on its involvement in mitochondrial homeostasis, autophagy regulation, synaptic plasticity, immune modulation, and metabolic signaling. Unlike previous reviews that addressed MDM2 mainly in oncogenesis or single neurological conditions, this work establishes a stage- and cell-type-specific framework of MDM2 regulation within the CNS. It distinguishes p53-dependent stress-surveillance mechanisms from p53-independent repair and metabolic pathways and introduces a therapeutic-window concept that balances neuroprotection with adaptive stress responses.Together, these perspectives position MDM2 as a dynamic molecular switch orchestrating neuronal fate, providing conceptual foundations for context-specific therapeutic strategies in neurological disease.