Pethani Yashvi, Pethani Neha, Shah Rima, Shah Jignesh, Shah Darshil
Department of Internal Medicine, Oak Hill Hospital, Brookville, Florida, USA.
Department of Dermatology, Karmdeep Hospital, Ahmedabad, Gujarat, India.
Catheter Cardiovasc Interv. 2026 Jan;107(1):326-341. doi: 10.1002/ccd.70325. Epub 2025 Nov 20.
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.
胆固醇结晶栓塞（CCE）是一种全身性血栓炎症性疾病（炎症途径和凝血级联反应的相互交织激活），其特征是胆固醇结晶（CCs）从动脉粥样硬化斑块栓塞到微血管中，导致多器官功能障碍。尽管其具有临床意义，但由于临床表现不特异和诊断挑战，CCE仍未得到充分诊断。本综述综合了当前关于CC诱导的中性粒细胞胞外陷阱（NET）形成在驱动内皮损伤、血栓形成和胃肠道癌症进展中的核心作用的证据，特别关注胃肠道恶性肿瘤。从机制上讲，CCs激活TLR4/9-NLRP3炎性小体级联反应，触发IL-1β释放和PAD4介导的组蛋白瓜氨酸化，最终导致NETosis。这些NETs通过促进内皮功能障碍、血小板粘附和免疫逃逸加剧血管损伤。在胃肠道癌症（如结直肠癌、肝细胞癌、胰腺癌）中，CCs通过诱导NET驱动的免疫抑制、细胞外基质降解和转移小生境形成来重塑肿瘤微环境（TME）。CCs、NETs和炎症之间的相互作用形成了一个自我延续的循环，使动脉粥样硬化、CCE和肿瘤转移恶化。针对这种胆固醇-NET-炎症轴的新兴治疗策略显示出前景。DNase I和肝素破坏NET支架，而PAD4抑制剂（如GSK484）阻断NET生成。秋水仙碱具有双重抗炎和抑制NETosis的作用，降脂药物（他汀类药物、PCSK9抑制剂）减轻CC负担。纳米疗法，如模拟HDL的纳米颗粒，提供靶向递送以恢复免疫监视。本综述强调需要个性化的、生物标志物引导的疗法来破坏致病性CC-NET轴，提出一种综合方法来减轻心血管和胃肠道肿瘤疾病中CC介导的损伤。
