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The inability to accurately predict the occurrence of postoperative cognitive dysfunction (POCD) among open-heart surgery patients leads to concerning increases in POCD cases. Preoperative circulating biomarkers are important to identify as they are non-invasive and could provide an early prediction of POCD development, allowing for earlier and more strategized interventions. However, to date, no robust circulating biomarkers have proven effective for preoperative POCD prediction. This systematic review aims to synthesize current evidence on preoperative protein profiling among POCD patients following open-heart surgery. Thus, a thorough literature search employing PubMed, EBSCOhost, Scopus, and Science Direct was carried out. This combination of keywords was used as part of the search strategy: ("Postoperative cognitive decline" OR "Postoperative cognitive disorders" OR "Postoperative cognitive dysfunction" OR "Postoperative cognitive complications") AND ("Thoracic Surgery" OR "Cardiac Surgery" OR "Heart Surgery") AND ("Protein expression" OR proteomic OR "Protein profiling"). Eight hundred and twenty-nine studies were retrieved and only clinical studies reporting the circulating preoperative differentially expressed Proteins (DEPs) in the POCD patients were selected. Six studies were selected following the inclusion and exclusion criteria. Only one preoperative DEP and four immediate postoperative DEPs were extracted from the studies. All four proteins were selected for analysis using DAVID, STRING, and Cytoscape software. Due to the very low number of proteins, no clusters have been identified. This systematic review demonstrates the lack of POCD preoperative biomarkers for open-heart-surgery patients. Thus, it is suggested that more studies can be conducted to fill this gap. [ABSTRACT FROM AUTHOR]