SARS-CoV-2 variants imprint distinct immune and metabolic signatures in host cells. Here, we show that the Delta and Omicron BA.4/BA.5 variants differentially regulate proinflammatory responses, oxidative stress, and iron metabolism in human primary M1 macrophages. Exposure to Delta - but not Omicron - strongly upregulated interleukin (IL)-6, IL-1β, and tumor necrosis factor alpha (TNF-α), increased reactive oxygen species (ROS) production, suppressed IL-10, and impaired viral clearance.

Exposure of macrophages with Delta was further associated with disrupted iron homeostasis, marked by concurrent upregulation of transferrin receptor 1 (TfR1), hypoxia-inducible factor 2α (HIF-2α), and iron regulatory protein 2 (IRP2), indicating altered iron regulation compared to Omicron-exposed macrophages. Delta also increased expression of the iron exporter ferroportin (FPN1) and reduced hepcidin secretion, consistent with altered iron trafficking and regulation. Confocal microscopy revealed elevated TfR1 expression in Delta-exposed cells with perinuclear accumulation. Blocking TfR-1 significantly reversed pro-inflammatory and oxidative stress in macrophages and reduced Delta-related viral load in macrophages and infectivity in co-cultures with susceptible Vero cells.

These findings suggest that exposure to the highly pathogenic Delta variant is associated with enhanced proinflammatory signaling and altered iron homeostasis, characterized by increased expression of iron regulatory proteins including TfR1 and FPN1, which may influence viral uptake and the persistence of intracellular viral RNA. Our study identifies a variant-specific link between SARS-CoV-2 infection, macrophage iron metabolism, and inflammatory signaling, and provides a foundation for further investigation of macrophage iron regulation in COVID-19.