GPSM3 (G protein signaling modulator 3) is a hematopoietic-restricted protein that functions as a negative regulator of G protein-coupled receptor signaling and inflammatory responses. Mechanistically, GPSM3 interacts with Gαi·GDP subunits through its GoLoco motifs to inhibit G protein activation 1, and associates with the C-terminal leucine-rich repeat domain of NLRP3 inflammasome components to suppress IL-1β production 2. Its subcellular localization is regulated through phosphorylation-dependent binding to 14-3-3 proteins, which stabilizes GPSM3 and confines it to the cytoplasm 1. Disease relevance: Genome-wide association studies identified GPSM3 polymorphisms (rs204989, rs204991) inversely associated with rheumatoid arthritis risk 3. Lower GPSM3 transcript abundance correlates with protection from inflammatory arthritis, potentially through reduced neutrophil chemotaxis toward leukotriene B4 and IL-8 4. GPSM3 was upregulated in tuberculoid leprosy lesions and associates with autophagy-mediated antimicrobial responses 5. Recent network analyses identified GPSM3 among genes with molecular commonalities between metabolic syndrome and multiple rheumatic diseases 6, and as a hub gene elevated in periodontitis tissues correlating with necroptosis 7. Clinical significance: GPSM3 represents a potential therapeutic target for inflammatory and rheumatic diseases, with genetic variants that decrease its expression conferring disease protection.