PLEK (pleckstrin) is the major protein kinase C substrate in platelets with roles extending to immune cell function and metabolic regulation. Mechanistically, PLEK regulates actin cytoskeleton organization, cortical actin dynamics, and protein kinase C signaling, particularly in thrombin-activated receptor pathways 1. Beyond its classical platelet function, PLEK serves as a differentiation marker for myeloid leukocytes and tumor-associated macrophages (TAMs), with strong expression specificity in pulmonary macrophages 1. In disease contexts, PLEK demonstrates significant prognostic value. In venous thromboembolism (VTE), PLEK is identified as a genetically regulated circulating protein with causal associations to VTE development 2. In non-small cell lung cancer, PLEK downregulation in TAMs correlates with better prognosis in adenocarcinoma (HR=0.71) 1. Conversely, in osteosarcoma, high PLEK expression associates with improved survival and correlates with increased infiltration of protective immune cells (macrophages, dendritic cells, CD4+ T cells), suggesting tumor-suppressive functions 3. PLEK serves as a biomarker in M2 macrophage-associated pathologies including chr2 rhinosinusitis with nasal polyps 4 and carotid atherosclerosis 5. These diverse associations suggest PLEK functions as an immune-metabolic hub regulating inflammation and cell differentiation across multiple disease states.