S100A8 is a calcium-binding protein primarily expressed in neutrophils and monocytes that functions as a critical alarmin modulating inflammatory responses 1. S100A8 predominantly acts as a heterodimer with S100A9 (S100A8/A9), which is released extracellularly upon immune cell activation and interacts with pattern recognition receptors TLR4 and RAGE to promote cell activation and recruitment 1. Mechanistically, S100A8/A9 suppresses mitochondrial complex I function by downregulating nuclear respiratory factor 1 expression, leading to impaired oxidative phosphorylation and cellular dysfunction 23. Clinically, S100A8/A9 plays pathogenic roles in multiple disease contexts. In myocardial ischemia-reperfusion injury, S100A8/A9 drives cardiomyocyte death and amplifies granulopoiesis via TLR4/inflammasome signaling 24. In sepsis, elevated S100A8/A9 triggers endothelial dysfunction and PANoptosis 3. S100A8/A9 also promotes tumor development and metastasis while suppressing anti-tumor immunity in melanoma through MDSC activation 56. Additionally, S100A8/A9 induces procoagulant platelet formation via GPIbα, contributing to thrombotic complications in COVID-19 7. Elevated S100A8/A9 serves as an independent prognostic biomarker in sepsis and correlates with poor outcomes in cardiovascular and malignant disease, making it a promising therapeutic target 36.