Gpsm1, also known as activator of G-protein signaling 3, is an accessory protein that modulates the G-protein signaling system. It is involved in multiple biological processes and associated with several pathways, such as those related to inflammation, metabolism, and cell-cycle regulation. Genetic models, especially KO/CKO mouse models, have been crucial for studying its functions [3].

In myeloid-specific Gpsm1-ablated mice, metabolic inflammation is repressed, protecting against high-fat diet-induced insulin resistance, glucose dysregulation, and liver steatosis. GPSM1 deficiency promotes TNFAIP3 transcription via the Gαi3/cAMP/PKA/CREB axis, inhibiting TLR4-induced NF-κB signaling in macrophages [1]. Mice lacking Gpsm1 in POMC neurons are protected against diet-induced obesity, glucose dysregulation, insulin resistance, and hepatic steatosis. Gpsm1 deficiency in these neurons enhances autophagy and leptin sensitivity through the PI3K/AKT/mTOR signaling, increasing POMC expression and α-MSH production, and enhancing sympathetic innervation and activity [2]. In an orthologous mouse model of autosomal dominant polycystic kidney disease, complete loss of Gpsm1 led to increased cyst progression and reduced renal function, and GPSM1 was shown to increase heteromeric polycystin-1/polycystin-2 ion channel activity via Gβγ subunits [3].

In conclusion, Gpsm1 plays essential roles in metabolic homeostasis, energy balance, and cyst progression in autosomal dominant polycystic kidney disease. The KO/CKO mouse models have significantly contributed to understanding its functions in these disease-related biological processes, providing potential therapeutic targets for metabolic disorders and polycystic kidney disease.