Pharmacological Inhibition of FKBP51 Mitigates Early Life Adversity‐Induced Social Deficits in Male Mice

ABSTRACT Early life adversity (ELA) is a major risk factor for psychiatric disorders, but targeted preventative strategies are lacking due to poor mechanistic insight. The FKBP51 protein, a co‐chaperone of the glucocorticoid receptor, is a key mediator of stress vulnerability. We tested if pharmacological inhibition of FKBP51 with the selective inhibitor SAFit2 prevents the long‐term consequences of ELA. Male mice exposed to ELA exhibited persistent deficits in social behavior, manifesting as social subordination in adolescence and adulthood. Early‐life SAFit2 treatment fully rescued these ELA‐induced behavioral impairments. Transcriptional profiling across six stress‐relevant brain regions revealed that SAFit2 normalized ELA‐driven gene expression changes, particularly in the medial prefrontal cortex and nucleus accumbens. Functional analysis showed the rescue converged on immunoregulatory and neuroactive ligand–receptor signaling pathways. Our findings establish FKBP51 as a critical pharmacological target for reversing the lasting impact of early life adversity on brain function, offering a path toward preventative treatment for ELA‐related psychopathology.