FKBP5/FKBP51-mediated signaling pathways in neuropsychiatric diseases: Insights for biomarker development and targeted therapies

The FK506-binding protein 5 gene encodes FKBP51, a molecular chaperone linked to the pathogenesis of neuropsychiatric diseases. Recent evidence shows that FKBP51 modulates activity of the HPA axis and GR-mediated feedback via dynamic interactions with GR, thereby influencing stress adaptation, inflammatory responses, and neuronal survival. This review systematically analyzes the mechanisms by which FKBP5 (and its encoded FKBP51) contributes to neuropsychiatric diseases and identifies shared pathways across these conditions. We further highlight key factors mediating disease variability and susceptibility: sex-, region-, and cell type-specific expression patterns of FKBP5/FKBP51, their temporal dynamics, genetic variants, epigenetic regulation, and gene-environment interactions. Additionally, we propose a "biphasic stress-response model" to conceptualize the temporal dynamics of FKBP5/FKBP51 expression during disease progression. Finally, we explore the translational potential of targeting FKBP51 signaling, and outline pharmacological strategies to modulate chaperone-dependent protein folding and stress pathways as novel therapeutic interventions.