Sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) is a secreted metallophosphoesterase belonging to the calcineurin-like phosphoesterase superfamily, closely related to acid sphingomyelinase (ASMase). Despite its name, SMPDL3A lacks activity against sphingomyelin and instead functions as a nucleotide phosphodiesterase, hydrolyzing nucleoside di- and triphosphates such as ATP. The enzyme contains a binuclear zinc center in its active site and exhibits an acidic pH optimum. The expression of SMPDL3A is induced by cholesterol loading and liver X receptor (LXR) ligands. Recent studies have identified SMPDL3A as a negative regulator of innate immunity by degrading 2'3'-cGAMP, thereby inhibiting the cGAS-STING signaling pathway.