Loss of function of ENT3 activates MAPK signaling through a noncanonical pathway. (1) Following target cell phagocytosis in an H syndrome monocyte, dysfunctional ENT3 prevents translocation of degraded nucleosides into the cytoplasm, resulting in lysosomal accumulation. (2) Accumulation of nucleosides activates TLR7/8, leading to downstream signaling. (3) TLR7/8 signaling stimulates ERK phosphorylation in an MEK-dependent manner. (4) Increased pERK activity alters the transcriptional program to increase production of proinflammatory cytokines, S100 proteins, and the prosurvival protein BCL2A1. (5) Inhibition of MEK signaling with trametinib effectively attenuates inflammatory cytokine production and resolves histiocytic lesions in a patient with H syndrome. IL, interleukin. Professional illustration by Somersault18:24.