PGGT1B (protein geranylgeranyltransferase type I subunit beta) catalyzes the transfer of geranyl-geranyl moieties from geranyl-geranyl pyrophosphate to cysteine residues in target proteins bearing the C-terminal CAAX motif 1. Known substrates include the small GTPases RAC1, RAC2, RAP1A, and RAP1B, making PGGT1B essential for protein prenylation-dependent signaling. Mechanistically, PGGT1B-mediated geranylgeranylation of RAC1 is critical for cytoskeletal dynamics and cell mechanics in intestinal epithelial cells. Deletion of Pggt1b in intestinal epithelial cells arrests epithelial cell shedding, causing cell overcrowding, tight junction redistribution, and ultimately epithelial leakage and spontaneous mucosal inflammation 2. In immune cells, PGGT1B deletion promotes myeloid-driven inflammation through CDC42 activation, leading to NF-κB pathway hyperactivation and increased proinflammatory cytokine secretion (IL-1β, IL-6, TNF-α) 3. Clinically, PGGT1B expression is significantly downregulated in psoriasis patients' peripheral blood mononuclear cells and correlates negatively with disease severity, suggesting diagnostic potential 4. Myeloid PGGT1B deficiency aggravates imiquimod-induced psoriasiform dermatitis in mice, while PGGT1B deletion in macrophages promotes keratinocyte proliferation and impairs differentiation 3. These findings identify PGGT1B as a key regulator of immune homeostasis and epithelial barrier integrity with implications for inflammatory bowel disease and psoriasis therapeutics.