GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE329nnn/GSE329962/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE329962GEOGSEfalsePathogenic IgG sialylation drives macrophage immunometabolic dysfunction and lung immunopathology via a Siglec-1–FcγR–VDAC1 axisImmunoglobulin G (IgG) Fc glycosylation critically regulates antibody effector functions, yet the pathogenic potential of early glycoform dynamics during acute viral infection remains poorly understood. Here, we identify a transient enrichment of sialylated IgG (Sia-IgG) during the early phase of SARS-CoV-2 infection that acts as a key driver of lung immunopathology. Contrary to the conventional anti-inflammatory role of sialylation, early-phase Sia-IgG fails to confer protection upon secondary viral challenge and instead aggravates lung injury despite reduced viral burden. Single-cell transcriptomic analysis of COVID-19 lungs reveals a selectively expanded SIGLEC1⁺ monocyte-derived macrophage population as a potential cellular target of this pathogenic signaling. Functional assays show that acute-phase IgG drives macrophage inflammatory infiltration in an FcγR-dependent manner. Moreover, acute-phase serum impairs phagocytic capacity and downregulates expression of the homeostatic marker CD206 in macrophages, indicative of a phenotypic shift toward a pro-inflammatory, dysfunctional state. Mechanistically, Sia-IgG coordinates the synergistic engagement of Siglec-1 and FcγRs, triggering mitochondrial immunometabolic collapse via VDAC1 oligomerization, excessive mitochondrial reactive oxygen species production, and impaired oxidative phosphorylation. Collectively, our findings define pathogenic IgG sialylation as a critical determinant of macrophage reprogramming, establishing a Siglec-1-FcγR-VDAC1 signaling axis that links humoral glycomic shifts to severe respiratory immunopathology during viral infection.2026/05/12GSE329962GSM9714090GSM9714092GSM9714091GSM9714094GSM9714093GSM9714096GSM9714095GSM9714098GSM971409729480329962Homo sapiens