MDM2 in the signaling pathways related to neurological diseases

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.