Background: Patients with angina and non-obstructive coronary artery disease (ANOCA) exhibit a high prevalence of mental stress-induced myocardial ischemia (MSIMI), a condition clinically associated with adverse cardiovascular outcomes. However, the pathophysiological mechanisms underlying this phenomenon remain poorly characterized, and the identification of specific biomarkers for early diagnosis represents an unmet clinical need. Aim: This investigation employs an integrative approach combining plasma proteomic profiling with clinical parameter analysis to elucidate the mechanistic basis of ANOCA and MSIMI. Through systematic biomarker screening, we aim to identify potential diagnostic indicators of MSIMI within ANOCA populations, ultimately constructing a biologically-grounded predictive model to facilitate early clinical detection. Results: Quantitative proteomic profiling identified 175 DEPs in ANOCA patients relative to controls, comprising 156 upregulated and 19 downregulated proteins. Pathway enrichment analysis revealed significant associations with adrenergic signaling in cardiomyocytes, complement/coagulation cascades, and metabolic regulation. Subsequent subgroup analysis demonstrated 95 DEPs distinguishing MSIMI+ from MSIMI- cases (47 upregulated; 48 downregulated). Those proteins are enriched inKEGG pathways related to cardiomyopathy pathways, PI3K-AKT signaling, HIF-1 signaling, pancreatic secretion, and metabolism. ELISA validation confirmed dysregulation of four mechanistically relevant candidates: insulin-like growth factor-binding protein-5 (IGFBP-5), insulin-like growth factor-1 (IGF-1), leptin receptor (LEPR), and epidermal growth factor receptor (EGFR). Thses four validated genes were also positive related with the SDS. Clinical test showed increased body mass index (BMI), free light chain ratio (Kappa/Lambda Ratio) and decreased cortisol were significantly associated with MSIMI+. Integration of proteomic signatures with clinical parameters yielded a diagnostic model demonstrating robust predictive capacity in MSIMI+ (AUC = 0.939). Conclusion：This study provides first evidence delineating the pathophysiological convergence of mental stress-induced myocardial ischemia (MSIMI) in ANOCA patients. It also validated specific plasma protein biomarkers and constructed diagnostic models in combination with clinical indicators. These findings establish a framework bridging molecular pathogenesis with clinical detection, proposing a non-invasive early diagnosis and a potential targeted intervention of MSIMI.