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

Overview

Authors: Joeri Bordes1,2, Xiuqi Ji3, Serena Gasperoni3, Choham Sudre‐Chinsky3, Amirali Kalbasi2, Daniela Harbich1, Cornelia Flachskamm1, Paula Fontanet3, Sowmya Narayan1, Manfred Uhr4, Christian Namendorf4, Camilla Bellone2, Alon Chen5, Felix Hausch6,7,8, Juan Pablo Lopez3, Mathias V Schmidt1
ORCID iDs: Joeri Bordes, Xiuqi Ji, Felix Hausch, Juan Pablo Lopez
  1. Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, Munich, Germany
  2. Department of Basic Neuroscience, University of Geneva, Geneva, Switzerland
  3. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
  4. Core Unit Analytics and Mass Spectrometry, Max Planck Institute of Psychiatry, Munich, Germany
  5. Department of Brain Science, Weizmann Institute of Science, Rehovot, Israel
  6. Department of Chemistry and Biochemistry, Clemens‐Schöpf‐Institute, Technical University Darmstadt, Darmstadt, Germany
  7. Center For Synthetic Biology, Technical University Darmstadt, Darmstadt, Germany
  8. Institute of Pharmaceutical and Biomedical Science (IPBS), Johannes Gutenberg University, Mainz, Germany
Institutions: University of Geneva (Switzerland); Max Planck Institute of Psychiatry (Germany); Karolinska Institutet (Sweden); Weizmann Institute of Science (Israel); Johannes Gutenberg University Mainz (Germany); Technische Universität Darmstadt (Germany)
Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany), volume 13, issue 48, article e76040
Dates: received 25 February 2026; accepted 28 May 2026; published online 9 June 2026; in print August 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1002/advs.76040 · PMID 42263247 · PMCID PMC13336721 · OpenAlex W7164073518
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), mouse (organism), cellular / molecular (subfield)
Methods: Statistics, fMRI & imaging, Physiology & signal measures, Machine learning
Keywords: fkbp5, glucocorticoid, glucocorticoid receptor, mediator, neuroscience, nucleus accumbens, prefrontal cortex, psychopathology, social defeat, transcriptome
MeSH: Social Behavior*, Stress, Psychological*, Tacrolimus Binding Proteins*, Animals, Brain, Male, Mice, Mice, Inbred C57BL, Tacrolimus Binding Protein 5 (* major topic)
Topic: Stress Responses and Cortisol (Behavioral Neuroscience, Neuroscience), according to OpenAlex
Funding: Federal Ministry of Education and Research (01GL1743C); European Research Council (101116064); Hjärnfonden (FO2024‐0038, FO2023‐0313); Svenska Sällskapet för Medicinsk Forskning (SG‐22‐0204); Swedish Society for Medical Research (SG-22-0204); Strategic Research Area Neuroscience; Swedish Research Council (2023-02499); Swedish Brain Foundation (FO2023-0313, FO2024-0038); Bundesministerium für Bildung und Forschung (01GL1743C); Vetenskapsrådet (2023‐02499)
Citations: cited by 2 papers (Europe PMC); 55 references in the paper

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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Data Availability Statement

The data that support the findings of this study are openly available in Gene Expression Omnibus at https://www.ncbi.nlm.nih.gov/geo/, reference number GSE318028 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE318028).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 16 authors, 10 keywords, 9 MeSH terms, 10 funders, 51 references.

Cite

This paper

Bordes, J., Ji, X., Gasperoni, S., Sudre‐Chinsky, C., Kalbasi, A., Harbich, D., Flachskamm, C., Fontanet, P., Narayan, S., Uhr, M., Namendorf, C., Bellone, C., Chen, A., Hausch, F., Lopez, J. P., & Schmidt, M. V. (2026). Pharmacological Inhibition of FKBP51 Mitigates Early Life Adversity-Induced Social Deficits in Male Mice. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 13(48), e76040. https://doi.org/10.1002/advs.76040

BibTeX

@article{bordes2026pharmacological,
author = {Bordes, Joeri and Ji, Xiuqi and Gasperoni, Serena and Sudre‐Chinsky, Choham and Kalbasi, Amirali and Harbich, Daniela and Flachskamm, Cornelia and Fontanet, Paula and Narayan, Sowmya and Uhr, Manfred and Namendorf, Christian and Bellone, Camilla and Chen, Alon and Hausch, Felix and Lopez, Juan Pablo and Schmidt, Mathias V},
title = {{Pharmacological Inhibition of FKBP51 Mitigates Early Life Adversity-Induced Social Deficits in Male Mice}},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = jun,
volume = {13},
number = {48},
pages = {e76040},
publisher = {Wiley},
issn = {2198-3844},
doi = {10.1002/advs.76040},
url = {https://doi.org/10.1002/advs.76040},
pmid = {42263247},
pmcid = {PMC13336721}
}

RIS

TY - JOUR
AU - Bordes, Joeri
AU - Ji, Xiuqi
AU - Gasperoni, Serena
AU - Sudre‐Chinsky, Choham
AU - Kalbasi, Amirali
AU - Harbich, Daniela
AU - Flachskamm, Cornelia
AU - Fontanet, Paula
AU - Narayan, Sowmya
AU - Uhr, Manfred
AU - Namendorf, Christian
AU - Bellone, Camilla
AU - Chen, Alon
AU - Hausch, Felix
AU - Lopez, Juan Pablo
AU - Schmidt, Mathias V
TI - Pharmacological Inhibition of FKBP51 Mitigates Early Life Adversity-Induced Social Deficits in Male Mice
T2 - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
J2 - Adv Sci (Weinh)
PY - 2026
DA - 2026/06/09
VL - 13
IS - 48
SP - e76040
SN - 2198-3844
PB - Wiley
DO - 10.1002/advs.76040
UR - https://doi.org/10.1002/advs.76040
LA - en
ER -

CSL-JSON

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