BACKGROUND: The potential pairwise connections among high-sensitivity C-reactive protein (hs-CRP), striatum-based circuits, and anhedonia in adolescents with depressive disorder are not clear. This study aimed to explore whether hs-CRP levels in adolescents with depressive disorder influence anhedonia via alterations of striatum-based functional connectivity (FC). METHODS: A total of 201 adolescents (92 with depressive episodes with anhedonia (anDE), 58 with DE without anhedonia (non-anDE), and 51 healthy controls (HCs)) underwent resting-state functional magnetic resonance imaging (fMRI) and completed the anhedonia subscale of the Children's Depression Inventory (CDI). hs-CRP levels were measured from peripheral blood samples in all DE patients. RESULTS: Compared with HCs, the anDE and non-anDE groups showed increased FC between the left dorsal caudate putamen (DCP_L) and bilateral cerebellum crus I, and decreased FC between the left ventral rostral putamen (VRP_L) and right parahippocampal cortex (PHC) (all p <
0.05). Only the non-anDE group exhibited increased FC between the right visual cortex (VC_R) and left cerebellum VI, VC_R and right fusiform gyrus (FG), and the left visual cortex (VC_L) and right inferior temporal gyrus (ITG) compared to HCs (all p <
0.05). Compared to the non-anDE group, the anDE group showed reduced FC between the VC_R and left cerebellum VI and between the DCP_L and right superior frontal gyrus (SFG) (all p <
0.05). Multiple regression analysis revealed that the FC between DCP_L and right SFG negatively predicted anhedonia severity (β = -0.288, p = 0.007) in the anDE group. Although hs-CRP levels had no direct effect for anhedonia, FC between the DCP_L and right SFG fully mediated the relationship between hs-CRP and anhedonia in the anDE group (effect = 0.184, Bootstrapping 95 % CI = 0.0156, 0.436). CONCLUSION: The findings suggest that hs-CRP influences anhedonia through a fully mediated pathway involving alterations in the frontostriatal network, contributing to a greater understanding of the neurobiological mechanisms underlying anhedonia.