Cholesterol Crystals and Neutrophil Extracellular Traps: Drivers of Thromboinflammation in Atherosclerosis and Gastrointestinal Cancers

ABSTRACT Cholesterol crystal embolism (CCE) is a systemic thromboinflammatory disorder (the intertwined activation of inflammatory pathways and coagulation cascades) characterized by the embolization of cholesterol crystals (CCs) from atherosclerotic plaques into microvasculature, leading to multiorgan dysfunction. Despite its clinical significance, CCE remains underdiagnosed due to nonspecific presentations and diagnostic challenges. This review synthesizes current evidence on the central role of CC‐induced neutrophil extracellular trap (NET) formation in driving endothelial injury, thrombosis, and gastrointestinal cancer progression with a specific focus on gastrointestinal malignancies. Mechanistically, CCs activate the TLR4/9‐NLRP3 inflammasome cascade, triggering IL‐1β release and PAD4‐mediated histone citrullination, which culminate in NETosis. These NETs exacerbate vascular damage by promoting endothelial dysfunction, platelet adhesion, and immune evasion. In gastrointestinal cancer (e.g., colorectal, hepatocellular, pancreatic), CCs remodel the tumor microenvironment (TME) by inducing NET‐driven immunosuppression, extracellular matrix degradation, and metastatic niche formation. The interplay between CCs, NETs, and inflammation creates a self‐perpetuating cycle that worsens atherosclerosis, CCE, and tumor metastasis. Emerging therapeutic strategies targeting this cholesterol‐NET‐inflammation axis show promise. DNase I and heparin disrupt NET scaffolds, while PAD4 inhibitors (e.g., GSK484) block NET generation. Colchicine demonstrates dual anti‐inflammatory and NETosis‐inhibitory effects, and lipid‐lowering agents (statins, PCSK9 inhibitors) mitigate CC burden. Nanotherapies, such as HDL‐mimetic nanoparticles, offer targeted delivery to restore immune surveillance. This review highlights the need for personalized, biomarker‐guided therapies to disrupt the pathogenic CC‐NET axis proposing an integrated approach to mitigate CC‐mediated damage in cardiovascular and gastrointestinal oncologic disease.