GPSM1 (G protein signaling modulator 1) is a guanine nucleotide dissociation inhibitor that functions as a receptor-independent activator of heterotrimeric G-protein signaling by maintaining Gi/o alpha subunits in their GDP-bound state 1. Beyond its canonical role in G-protein regulation, GPSM1 has emerged as a multifunctional protein with significant pathological relevance. In atherosclerosis, myeloid GPSM1 promotes monocyte activation and macrophage infiltration through the cAMP/PKA/KLF4/PMP22 axis regulating p38/ERK MAPK signaling, with myeloid-specific ablation protecting mice against disease progression 2. In colorectal cancer, elevated GPSM1 drives anti-PD-1 immunotherapy resistance by stabilizing through USP9X-mediated deubiquitination, leading to M2 macrophage polarization via MEIS3-dependent CSF1 expression; ruxolitinib targeting GPSM1 restores immunotherapy efficacy 3. GPSM1 also promotes CRC metastasis through cooperation with MMP19 to drive epithelial-mesenchymal transition and cell proliferation 4. In B-cell acute lymphoblastic leukemia, GPSM1 overexpression supports tumor growth via ADCY6-RAPGEF3-JNK signaling 5. Additionally, GPSM1 variants associate with type 2 diabetes through skeletal muscle expression regulation 6 and premature ovarian insufficiency through cAMP-PKA-CREB pathway suppression 7. These findings establish GPSM1 as a promising therapeutic target across multiple diseases.