Icariin enhances contextual fear extinction via modulation of platelet activation and ECM-associated signaling in the hippocampus: A multiomics perspective

Impaired fear extinction is a hallmark feature of stress- and anxiety-related disorders. Icariin (ICA), a flavonoid derived from Epimedium, exhibits neuroprotective effects in various preclinical models, but its role in fear modulation remains unclear. In this study, we examined the impact of ICA on contextual fear extinction in a rat model subjected to foot shock (FS). Proteomic and metabolomic profiling of the hippocampus was conducted using data-independent acquisition (DIA) proteomics and untargeted metabolomics. ICA treatment significantly enhanced fear extinction in FS-exposed rats. Proteomic analysis identified 175 differentially expressed proteins, with enrichment in platelet activation and extracellular matrix (ECM)-associated pathways. Metabolomic profiling revealed 50 upregulated and 229 downregulated metabolites, highlighting the involvement of the sphingolipid signaling pathway. Among the altered proteins, Myl9, Gp1ba, Parvb, and Prkaca emerged as key candidates implicated in ICA’s effects on fear extinction, with Myl9 and Prkaca levels significantly correlated with freezing behavior. Integrative analysis further linked multiple differential metabolites, including (±)12,13-DiHOME, to Myl9 and Prkaca expression. These findings provide novel insights into the molecular mechanisms underlying ICA’s therapeutic potential for fear-related neuropsychiatric disorders.