ILRUN (inflammation and lipid regulator with UBA-like and NBR1-like domains) is a multi-functional regulator of innate immunity and lipid metabolism. Structurally, ILRUN contains conserved UBA-like and NBR1-like domains essential for its biological functions 1. As a negative regulator of antiviral immunity, ILRUN inhibits type I interferon production by blocking IRF3-dependent transcription of IFNA, IFNB, and TNF 1. It accomplishes this by preventing IRF3 recruitment to type I interferon promoters while reducing nuclear coactivator levels 1. ILRUN also negatively regulates the renin-angiotensin-aldosterone system by downregulating ACE2 and coreceptors TMPRSS2 and CTSL 2. In lipid metabolism, ILRUN promotes hepatic lipoprotein production through ubiquitin-binding interactions with PPARα, regulating genes downstream of lipid transcription factors 3. ILRUN expression positively correlates with atherosclerosis development through both lipid-dependent and lipid-independent mechanisms, including suppression of macrophage efferocytosis 4. Clinically, ILRUN variants associate with coronary artery disease and dyslipidemia 3, systemic lupus erythematosus (with reduced ILRUN expression in patients) 5, frailty 6, and shared COVID-19/coronary heart disease pathology 7. As a SARS-CoV-2 antiviral factor, ILRUN overexpression suppresses viral replication 2.