{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T05:02:33Z","timestamp":1791435753231,"version":"4.3.3"},"reference-count":92,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>FK506-binding protein 51 (FKBP51) is a pivotal molecular chaperone and scaffolding protein that integrates and modulates multiple signaling pathways\u2014including those involving HSP90, the glucocorticoid receptor, AKT, and NF-\u03baB\u2014through its FK1, FK2, and TPR domains, thereby playing a central role in the maintenance of central nervous system (CNS) homeostasis. This review systematically elaborates on the pathological mechanisms and therapeutic potential of FKBP51 in a variety of CNS disorders. In neurodegenerative diseases, FKBP51 promotes aberrant aggregation of Tau protein via the HSP90 complex, exacerbating the pathological progression of Alzheimer\u2019s disease; in Parkinson\u2019s disease, it influences neuronal survival through interaction with the PINK1\/AKT signaling pathway; while in Huntington\u2019s disease, it impairs the clearance of mutant huntingtin (mHTT) protein. In models of ischemic stroke, upregulation of FKBP51 enhances autophagy and inflammatory responses through pathways such as AKT\/FoxO3, thereby amplifying brain injury. In glioma, FKBP51 exhibits a context-dependent dual role: it may exert tumor-suppressive effects by inhibiting Akt, while its splice variant FKBP51s can regulate PD-L1 expression, promoting tumor immune evasion and therapy resistance. Emerging highly selective small-molecule inhibitors, gene-editing technologies, and novel applications of conventional drugs targeting FKBP51 have demonstrated significant interventional potential in preclinical studies. In summary, FKBP51 constitutes a pleiotropic signaling node, positioning it as a prime therapeutic target for a broad spectrum of CNS disorders.<\/jats:p>","DOI":"10.3389\/fnmol.2025.1725945","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T08:10:33Z","timestamp":1768205433000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Role of FK506 binding protein 51 in central nervous system diseases"],"prefix":"10.3389","volume":"18","author":[{"given":"Haokun","family":"Peng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhao","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmei","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rentang","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longhai","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e95992","DOI":"10.1371\/journal.pone.0095992","article-title":"Mitochondria-nucleus shuttling FK506-binding protein 51 interacts with TRAF proteins and facilitates the RIG-I-like receptor-mediated expression of type I IFN.","volume":"9","author":"Akiyama","year":"2014","journal-title":"PLoS One"},{"key":"B2","doi-asserted-by":"publisher","first-page":"107623","DOI":"10.1016\/j.pharmthera.2020.107623","article-title":"FK506 binding proteins and inflammation related signalling pathways; basic biology, current status and future prospects for pharmacological intervention.","volume":"215","author":"Annett","year":"2020","journal-title":"Pharmacol. 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