Objective <p>This study explored the role of X-box binding protein 1 (XBP1), phospholipase A2 (PLA2), and B-type natriuretic peptide (BNP) as biomarkers for diagnosing and predicting myocardial injury in patients with ST-segment elevation acute myocardial infarction (STEMI).</p> Methods <p>This prospective cohort study enrolled 283 adult patients with Acute Coronary Syndrome (ACS) admitted to Tianjin Third Central Hospital between October 2021 and October 2022. Patient selection followed strict criteria: inclusion required ACS diagnosis or high ACS risk with informed consent; exclusion criteria were history of myocardial infarction, ejection fraction &lt; 30%, or comorbidities (e.g., cardiomyopathy, renal disease). Patients were divided into STEMI and non-STEMI/unstable angina groups based on electrocardiogram findings. Serum levels of XBP1, PLA2, and other related indicators were measured using enzyme-linked immunosorbent assay (ELISA) kits. The relationships between these biomarkers and myocardial injury were analyzed.</p> Results <p>XBP1 and PLA2 levels were significantly elevated in patients with myocardial ischemia-reperfusion injury (MIRI), myocardial injury, and those undergoing intervention. Recombinant human BNP (rhBNP) treatment was associated with lower XBP1 and PLA2 levels 24&#xa0;h post-surgery. Logistic regression analysis identified smoking history, neutrophil percentage, sICAM-1, and PLA2 as independent risk factors for myocardial injury. XBP1, PLA2, and BNP levels were independently related to myocardial injury and showed significant positive correlations with each other. ROC curve analysis indicated that XBP1 and PLA2 levels had significant diagnostic efficacy for postoperative myocardial injury, with the combined diagnostic approach yielding the best performance.</p> Conclusion <p>Pre-treatment serum PLA2 and XBP1 levels, alone or in combination, may serve as significant predictors of myocardial injury in ACS patients undergoing PCI. rhBNP may protect the myocardium and improve cardiac function by reducing XBP1 and PLA2 levels. These findings suggest that pre-treatment serum PLA2 and XBP1 levels could be used as practical biomarkers for risk stratification in ACS patients undergoing PCI, aiding clinicians in decision-making regarding rhBNP therapy. Further studies are needed to validate these results and integrate them into clinical guidelines.</p>