The multifaceted roles of the transcription factor SP1 in the pathogenesis of Alzheimer's disease: From molecular regulation to therapeutic targets.

UNLABELLED: Alzheimer's disease (AD) is driven by interrelated pathologies, including the accumulation of amyloid β (Aβ), tau pathology, chronic neuroinflammation, and oxidative stress (OS). These pathological processes collectively lead to progressive neurodegeneration. The transcription factor specificity protein 1 (SP1) functions as a key transcriptional regulator in AD pathogenesis. By binding to GC-box elements, SP1 promotes Aβ production and tau hyperphosphorylation. It also activates microglia, perpetuating neuroinflammation; disrupts oxidative balance; and ultimately induces neuronal death through ferroptosis and apoptosis. Furthermore, environmental toxins exacerbate AD progression by enhancing SP1-DNA binding activity via epigenetic mechanisms such as DNA methylation and histone modifications. SP1 activity is tightly controlled by diverse post-translational modifications, which adds another layer of complexity to its function. Small-molecule inhibitors, natural compounds, and epigenetic interventions can modulate the SP1-regulated network, thereby ameliorating key pathological features and demonstrating broad therapeutic potential. Future efforts must address developing brain-targeted delivery systems and precise epigenetic editors for effective clinical translation. HIGHLIGHTS: SP1 functions as a master transcriptional hub in Alzheimer's disease, simultaneously driving amyloid beta production, tau hyperphosphorylation, neuroinflammation, oxidative stress, and ferroptotic cell death.Environmental toxins epigenetically activate SP1 via altered DNA methylation and histone modifications, establishing a molecular link between external risk factors and late-onset Alzheimer's pathogenesis.Post-translational modifications and microRNAs tightly regulate SP1 activity; their dysregulation in AD amplifies pathogenic gene expression networks.Small-molecule inhibitors and natural compounds targeting SP1 demonstrate multi-pathway therapeutic potential in preclinical Alzheimer's models.Cell-type-specific SP1 functions, compensatory upregulation of SP3/SP4 family members, and limited blood-brain barrier penetration present major challenges for clinical translation.