High Serum Uric Acid Promotes Metastasis by Disrupting Endothelial Functions Through the NF-κB-NOX4 Pathway

Uric acid (UA), the end product of purine metabolism, is elevated in hyperuricemia—a pathological condition linked to Western diets and associated with gout, cardiovascular diseases, chronic kidney disease, and cancer. While the role of hyperuricemia in these disorders is well recognized, its contribution to cancer metastasis remains unclear. Here, we investigate the impact of UA on endothelial cells (ECs) and its implications for metastasis. Our RNA-seq analysis of UA-treated ECs revealed substantial transcriptional changes, including upregulation of adhesion molecules and proinflammatory cytokines, alongside downregulation of genes critical for endothelial functions and vascular development. UA exposure disrupted EC barrier properties and facilitated the transendothelial invasion of breast cancer cells, implicating endothelial dysfunction as a key mediator of metastasis. Mechanistically, we identified that elevated reactive oxygen species (ROS) levels directly contributed to UA-mediated endothelial dysfunction: UA activated the NF-κB-NOX4 signaling axis, leading to abnormal ROS production. Pharmacologic inhibition of NF-κB attenuated ROS generation, endothelial activation, and junctional breakdown in vitro and in vivo. In a hyperuricemia mouse model, breast cancer cells exhibited increased lung metastases, despite UA having no direct effect on cancer cell migration. Given that extravasation is a rate-limiting step in lung metastasis, compromised endothelium can be a major contributor to metastasis in hyperuricemia. These findings reveal a previously unrecognized link between UA and cancer metastasis through endothelial oxidative stress. Targeting UA-induced vascular alterations may represent a novel therapeutic strategy to mitigate metastasis risk and highlights the importance of UA management in preserving vascular health.