IFI30 protects against atherosclerotic progression by reducing macrophage foam cell formation and oxidative stress

Atherosclerosis (AS) is a chronic progressive inflammatory vascular disease and the main pathological basis of cardiovascular and cerebrovascular diseases worldwide. Interferon-gamma-inducible lysosomal thiol reductase (IFI30) is a reductase involved in antigen processing and redox regulation, but its role in AS remains unclear. This study aimed to investigate the expression and function of IFI30 in macrophages within AS plaques and to explore its potential mechanisms in regulating macrophage foam cell formation and oxidative stress. To establish an AS model, we fed 8-week-old male ApoE −/− mice a high-fat diet for 16 weeks. We then constructed a mouse model with macrophage-biased Ifi30 knockdown by injecting adeno-associated virus (AAV2/9) carrying the F4/80 promoter and ZsGreen-labeled shIFI30 via the tail vein. We used Western blot, RT-qPCR, and immunofluorescence (IF) to detect IFI30 expression in aortic plaques and in THP-1-derived foam cells induced by ox-LDL (80 µg/mL, 48 h). These findings were further validated using transcriptomic and single‑cell RNA‑seq data from human carotid atherosclerotic plaques. We evaluated the effects of IFI30 overexpression and knockdown on macrophage foam cell formation and oxidative stress using Oil Red O staining, ROS staining, MDA detection, and Western blot. The results showed that IFI30 expression was significantly increased in mouse and human carotid atherosclerotic plaques macrophages, as well as in THP-1-derived foam cells. Overexpression of IFI30 in THP-1-derived macrophages reduced foam cell formation and oxidative stress, accompanied by downregulation of mitochondrial ACAT1 and activation of the KEAP1/NRF2 pathway (manifested as increased total NRF2 and upregulation of HO-1, xCT, and SOD2). In vivo experiments further confirmed that macrophage-biased Ifi30 knockdown increased plaque area, reduced collagen content, and aggravated AS progression. In summary, IFI30 protects against AS progression by reducing macrophage foam cell formation and oxidative stress, suggesting that IFI30 is a potential protective factor and candidate target for further investigation in AS.