Hong GUO, Mengyu WANG, Ranli LI, Ying ZHANG, Xiaoyan MA, Hongjun TIAN, Ronghuan JIANG, Ximing CHEN, Chuanjun ZHUO
Psychiatry and Clinical Psychopharmacology - 2026;36(3):259-269
Background: Rapamycin (RAPA) is an inhibitor of the mammalian target of rapamycin (mTOR) that may modulate neuropsychiatric conditions. The global prevalence of psychiatric disorders is increasing due to growing socioeconomic stressors. Despite the promising therapeutic indications of RAPA, the precise molecular mechanisms underlying the effects of RAPA on schizophrenia are unclear. This study investigates anti-schizophrenia mechanisms of RAPA using network pharmacology and molecular docking. Methods: Potential pharmacological targets of RAPA were identified by searching the SwissTargetPrediction, GeneCards, and Similarity Ensemble Approach databases. Schizophrenia-related targets were identified by searching GeneCards and Online Mendelian Inheritance in Man. Bioinformatics analysis (including analyses of protein-protein interaction networks and enrichment analyses) was conducted to identify core targets and signaling pathways. Molecular docking simulations were conducted to assess drug binding affinities to core targets. Results: Cross-referencing 4013 targets linked to schizophrenic pathology with 1954 RAPA-associated targets yielded 749 shared targets. Protein-protein interaction network analysis revealed the following core targets: interleukin-6 (IL-6), interferon-gamma, IL-10, IL-4, IL-2, IL-1 beta (IL-1B), tumor necrosis factor, IL-5, IL-17A, and IL-1A. Functional enrichment assessments revealed that signal transduction, positive regulation of transcription by RNA polymerase II, positive regulation of gene expression, and positive regulation of DNA-templated transcription are critical biological processes involved in RAPA antipsychotic effects. Pathway analysis revealed that the PI3K-AKT signaling cascade is a central mechanism mediating the effects of RAPA. Molecular docking simulations confirmed strong binding affinities between RAPA and the core targets. Conclusion: Rapamycin may modulate cytokine networks and PI3K-AKT/mTOR signaling pathways implicated in schizophrenia. These in-silico findings are hypothesis-generating and require experimental and clinical validation.
