{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T02:17:16Z","timestamp":1788229036243,"version":"build-2803163510"},"reference-count":75,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Alzheimer\u2019s disease (AD) is the most common neurodegenerative disorder, and current therapies provide only limited symptomatic relief without effectively slowing its progression. Increasing evidence suggests that aberrant activation of the Janus kinase\/signal transducer and activator of transcription (JAK\/STAT) signaling cascade contributes to AD-associated neuroinflammation. This study investigated the therapeutic potential and molecular mechanisms of JAK inhibitors in AD using integrated bioinformatics and network pharmacology approaches. Materials and Methods: Potential anti-AD targets of JAK inhibitors were identified using the SwissTargetPrediction and GeneCards databases. Functional enrichment, protein\u2013protein interaction (PPI) analysis, transcriptomic validation using public datasets, regulatory network construction, molecular docking, normal mode analysis (NMA), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction were performed to investigate the potential mechanisms of action of these drugs in AD. Results: Our analysis identified 163 shared targets between JAK inhibitors and AD. Enrichment analysis revealed that these genes were primarily involved in protein phosphorylation and were enriched in key signaling pathways, including the neurotrophin, phosphoinositide 3-kinase\/protein kinase B (PI3K\/Akt), and mitogen-activated protein kinase (MAPK) signaling pathways. PPI analysis identified AKT1, BCL2, SRC, STAT3, and TNF as five highly ranked hub targets across multiple topological algorithms. Transcriptomic validation confirmed significantly higher expression of these targets in the prefrontal cortex of individuals with AD compared with normal subjects. Molecular docking indicated that pacritinib and momelotinib showed relatively favorable predicted interactions with the hub proteins, while NMA revealed differences in the predicted flexibility of the docked complexes. Furthermore, ADMET prediction showed that pacritinib possesses favorable pharmacokinetic properties for the treatment of AD. Conclusions: Collectively, these findings provide mechanistic insights into the potential effects of JAK inhibitors in AD and identify pacritinib as a computationally prioritized candidate that warrants experimental validation in appropriate AD models. However, as this study is based solely on computational analyses without wet-lab validation, the findings should be considered hypothesis-generating in silico evidence, and the potential safety concerns of pacritinib require further investigation.<\/jats:p>","DOI":"10.3390\/medicina62091674","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T01:05:26Z","timestamp":1788224726000},"page":"1674","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Computational Repurposing of Janus Kinase Inhibitors as Potential Therapeutic Candidates for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0567-2562","authenticated-orcid":false,"given":"Ly Thi Huong","family":"Nguyen","sequence":"first","affiliation":[{"name":"Institute of Theoretical and Applied Research, Duy Tan University, Hanoi 100000, Vietnam"},{"name":"College of Medicine and Pharmacy, Duy Tan University, Da Nang 550000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6469-9514","authenticated-orcid":false,"given":"Mai Thi","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Faculty of Chemical Engineering, Ho Chi Minh City University of Technology (HCMUT), 268 Ly Thuong Kiet Street, Dien Hong Ward, Ho Chi Minh City 72511, Vietnam"},{"name":"Vietnam National University Ho Chi Minh City, Linh Trung Ward, Ho Chi Minh City 71308, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4908-1185","authenticated-orcid":false,"given":"Thai Uy","family":"Nguyen","sequence":"additional","affiliation":[{"name":"College of Health Sciences, VinUniversity, Hanoi 100000, Vietnam"},{"name":"Vinmec International Hospital, Hanoi 100000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_2","first-page":"1","article-title":"Amyloid-beta: A crucial factor in Alzheimer\u2019s disease","volume":"24","author":"Sabermarouf","year":"2015","journal-title":"Med. 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