Our understanding of the functions of neutral
sphingomyelinase (N-SMase) signaling has advanced over the past decade. In this review, we focus on the roles and regulation of N-SMase 1, N-SMase 2, N-SMase 3, an
enzyme that generates the bioactive
lipid ceramide through the hydrolysis of the
membrane lipid sphingomyelin. A large body of work has now implicated N-SMase 2 in a diverse set of cellular functions, physiological processes, and disease pathologies. We focus on different aspects of this
enzyme's regulation from transcriptional, post-translational, and biochemical. Furthermore, we expected N-SMase involvement in cellular processes including inflammatory signaling, cell growth, apoptosis, and
tumor necrosis factor which in turn play important roles in pathologies such as
cancer metastasis, variable disease, and other organ system disorders. Lastly, we examine avenues where targeted N-SMase inhibition may be clinically beneficial in disease scenarios.