biostudies-literatureWang ZSTI2030-Major ProjectsShanghai Municipal Commission of Science and Technology ProgramShanghai Education Commission Research and Innovation Program2183https://www.ebi.ac.uk/biostudies/studies/S-EPMC12467129biostudies-literatureUnknown13(9)<b>Background:</b> Major depressive disorder (MDD) is a prevalent and disabling psychiatric illness with complex etiologies involving both genetic and environmental factors. While environmental stress is a known risk factor of MDD, the molecular mechanisms linking stress exposure to persistent depressive phenotypes remain incompletely understood. <b>Methods</b>: We established a 24-hour restraint stress-induced depression model in mice and performed integrated transcriptomic and proteomic analyses of the medial prefrontal cortex (mPFC) to investigate stress-related molecular alterations. <b>Results</b>: Behavioral assessments confirmed persistent depression-like phenotypes, including anhedonia and behavioral despair, lasting up to 35 days post-stress. RNA sequencing identified differentially expressed genes related to dopaminergic signaling and oxidative stress. Proteomic analysis identified 105 differentially expressed proteins involved in immune response and energy metabolism. Integrated multi-omics analysis highlighted convergent disruptions in immune regulation, metabolism, and epigenetic processes. Notably, clemastine exerts its antidepressant-like effects in part by mitigating neuroinflammation and preserving mitochondrial function. <b>Conclusions</b>: These findings provide novel insights into the molecular basis of stress-induced depression and suggest that clemastine is a potential therapeutic candidate.BiomedicinesIntegrated Multi-Omics Analysis Reveals Immune and Metabolic Dysregulation in a Restraint Stress-Induced Depression Model.PMC124671292022ZD02049002019-01-07-00-02-E0003723490712600Li WLi YZhao QWang XWang ZLan ZfalseIntegrated Multi-Omics Analysis Reveals Immune and Metabolic Dysregulation in a Restraint Stress-Induced Depression Model.<b>Background:</b> Major depressive disorder (MDD) is a prevalent and disabling psychiatric illness with complex etiologies involving both genetic and environmental factors. While environmental stress is a known risk factor of MDD, the molecular mechanisms linking stress exposure to persistent depressive phenotypes remain incompletely understood. <b>Methods</b>: We established a 24-hour restraint stress-induced depression model in mice and performed integrated transcriptomic and proteomic analyses of the medial prefrontal cortex (mPFC) to investigate stress-related molecular alterations. <b>Results</b>: Behavioral assessments confirmed persistent depression-like phenotypes, including anhedonia and behavioral despair, lasting up to 35 days post-stress. RNA sequencing identified differentially expressed genes related to dopaminergic signaling and oxidative stress. Proteomic analysis identified 105 differentially expressed proteins involved in immune response and energy metabolism. Integrated multi-omics analysis highlighted convergent disruptions in immune regulation, metabolism, and epigenetic processes. Notably, clemastine exerts its antidepressant-like effects in part by mitigating neuroinflammation and preserving mitochondrial function. <b>Conclusions</b>: These findings provide novel insights into the molecular basis of stress-induced depression and suggest that clemastine is a potential therapeutic candidate.2025-01-01T00:00:00Z2025 Sep2026-05-02T03:10:57.68Z2026-05-02T03:07:50.669ZS-EPMC124671294100774610.3390/biomedicines13092183