Gliomas are characterized by high mortality and disability rates. Cancer-testis antigens (CTAs) are among the most promising therapeutic targets for combating cancer. While several CTAs have been associated with the development and progression of gliomas, the role of ATPase family AAA domain-containing protein 2 (ATAD2) in this context has not been thoroughly investigated. In this study, both in vitro and in vivo experiments validated the role of ATAD2 in enhancing malignant phenotypes. The LN229 cell lines were employed for RNA-seq and proteomics to uncover downstream targets of ATAD2. Results showed that elevated ATAD2 expression was noted in glioblastoma (GBM). ATAD2 knockdown significantly reduced the proliferation, migration, and invasion capabilities of GBM cells, while its overexpression had the opposite effect. The knockdown of ATAD2 led to a decrease in subcutaneous tumor size and weight, a reduction in Ki67 expression, and an extension of survival in mice bearing intracranial in situ tumors. Mechanistically, a positive feedback loop involving ATAD2 and E2F transcription factor 1 (E2F1) was identified to enhance the transcriptional activation of pyruvate dehydrogenase kinase 1 (PDK1). Notably, the expression levels of these genes were found to be positively correlated, with patients exhibiting high levels of these genes tending to have poorer prognoses. These findings demonstrate that ATAD2 plays a pivotal role in the malignant progression of glioma and synergizes with E2F1 to promote PDK1 expression, suggesting its potential as a therapeutic target for glioma.

The nervous system, as the organ responsible for sensory information processing and motor control, executes advanced functions such as language, learning, cognition, and emotion. Cellular senescence, neuroinflammation, and synaptic plasticity decline in the central nervous system (CNS) constitute core pathological mechanisms underlying neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS) etc. Senescent neurons and glial cells secrete pro-inflammatory cytokines and reactive oxygen species (ROS), which amplify neuroinflammatory responses, accelerate cellular senescence, and disrupt synaptic homeostasis. Neuroinflammation directly eliminates synapses or inhibits synaptic plasticity-related molecules via immune signaling pathways and complement activation. Concurrently, synaptic dysfunction exacerbates metabolic dysregulation and pathological protein propagation, further driving neuronal senescence and inflammatory amplification, forming a self-reinforcing vicious cycle. Although AD, PD and MS exhibit distinct pathological features and regional brain involvement, both adhere to a tripartite pathological framework centered on "senescence-inflammation-synaptic damage". This review systematically explores the multidimensional impact of CNS aging, dissects the driving role of neuroinflammation, and highlights the pivotal position of synaptic plasticity decline in disease progression. These insights provide a scientific foundation for developing unified theoretical models of neurodegenerative diseases and multi-target therapeutic strategies.