Mitigating psychological stress-induced cardiac injury: The impact of CB2R agonists on endoplasmic reticulum stress and mitophagy.

BACKGROUND: Psychological stress is a recognized contributor to cardiac injury and disease; however, the molecular mechanisms underlying this relationship remain incompletely understood, and effective therapeutic strategies are still limited. MATERIALS AND METHODS: DEGs were identified from our sequencing data and GEO datasets, intersected with ER stress/mitophagy-related genes, and then prioritized by machine-learning and network analyses; pathway activity, immune signatures, molecular subtypes, and miRNA-mRNA interactions (DIANA-TarBase) were further characterized and experimentally validated. RESULTS: In cardiac injury induced by psychological stress, 38 differentially expressed ER stress- and mitophagy-related genes were identified. Through methods such as LASSO regression, four key genes-Foxo3, Pparg, Sirt1, and Stat3-were selected. ROC analysis of the four-gene phenotype score showed strong discrimination in the test dataset (AUC = 0.917 for control vs. stress; AUC = 0.938 for stress vs. CB2R-agonist treatment) and moderate discrimination in the external validation cohort GSE68077 for the comparison of controls versus 5dayStress-1dayRest samples (AUC = 0.720). Correlation analysis revealed that Sirt1 exhibited significant positive correlations with CD56bright natural killer cells, MDSCs, and Type 1 T helper cells. Pparg showed a notable positive association with Type 1 T helper cells, while γδ T cells showed significant negative correlations with Stat3, Sirt1, Pparg, anRd Foxo3. Treatment with a cannabinoid type 2 receptor (CB2R) agonist notably downregulated the expression of these four key genes. CONCLUSION: This study provides mechanistic insight into molecular processes underlying psychological stress-induced cardiac injury. The identified four-gene module may serve as an exploratory molecular signature and a starting point for evaluating CB2R agonism as a modulator of ER stress and mitophagy.