Background and objective <p>To investigate the role and mechanism of epithelial sodium channel (ENaC) in the inflammatory response of dendritic cells (DCs) induced by high fat, oxidized low-density lipoprotein (ox-LDL) was employed to trigger an inflammatory response in DCs.</p> Method <p>DCs were cultured in vitro and induced with high fat using ox-LDL, with or without benzamil (a specific ENaC blocker). Changes in protein expression levels of ENaC, calcineurin (CaN), total nuclear factor of activated T-cells 1 (t-NFATc1) and phospho-NFATc1 (p-NFATc1) in DCs were determined by western blot. Changes in mRNA levels of inflammatory factors, matrix metalloproteinase 9 (MMP9), and tissue inhibitor of metalloproteinases 2 (TIMP2) in DCs were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Changes in intracellular [Ca²⁺] in DCs were detected using a calcium fluorescent probe.</p> Results <p>Ox-LDL upregulated the protein expression levels of α-ENaC and γ-ENaC in DCs. Benzamil reduced the release of inflammatory factors in ox-LDL-induced DCs. Inhibition of ENaC significantly decreased the mRNA expression of MMP9 and increased TIMP2 in ox-LDL-induced DCs. Inhibition of ENaC significantly decreases the aberrant increase in [Ca²⁺] in ox-LDL-induced DCs, and also significantly decreases the increased protein expression levels of CaN and its downstream t-NFATc1, however, the protein level of p-NFATc1 was significantly elevated.</p> Conclusion <p>ENaC in DCs critically mediates high-fat-induced inflammation. The mechanism may involve ox-LDL upregulating α-ENaC and γ-ENaC in DCs, leading to increased intracellular [Na⁺], which elevates intracellular [Ca²⁺] via Na⁺/Ca²⁺ exchanger (NCX). This subsequently triggers the inflammatory response through the Ca²⁺-CaN-NFATc1 signaling pathway. This research provides new evidence for the theoretical basis of immunotherapy for atherosclerosis (AS).</p>