SMPDL3A is a secreted zinc-dependent phosphodiesterase that functions as a negative regulator of innate immunity 1. It catalyzes the linearization of 2',3'-cGAMP into 2'5'-bond pGpA and further hydrolyzes this product to generate GpA, thereby suppressing cGAS-STING signaling 1. Beyond cGAMP degradation, SMPDL3A exhibits in vitro nucleotide phosphodiesterase activity with nucleoside triphosphates (ATP) and diphosphates, with lower activity against nucleoside diphosphates and no activity against monophosphates 2. It also processes CDP-choline and CDP-ethanolamine but lacks sphingomyelin phosphodiesterase activity, despite structural homology to acid sphingomyelinase 2. Expression of SMPDL3A is upregulated by liver X receptor ligands and cholesterol loading in macrophages, linking lipid metabolism to immune regulation 23. N-glycosylation is essential for SMPDL3A stability, secretion, and enzymatic activity 4. In cancer contexts, SMPDL3A promotes hepatocellular carcinoma growth and metastasis through the LRPPRC pathway 5. The protein represents a critical intersection between cholesterol homeostasis and cGAS-STING-mediated inflammation 6.