Peripheral immune-redox signatures associate with cortical network alterations in anhedonic depression

Anhedonia is a core feature of major depressive disorder (MDD), yet links between peripheral molecular signatures and cortical network architecture remain poorly defined. We enrolled 210 participants, including 56 unmedicated MDD patients with high-anhedonia (HA), 61 with low-anhedonia (LA), and 93 healthy controls (HC). Morphometric similarity networks (MSNs) from structural MRI were compared between HA and LA. MSNs index individual-level network organization by quantifying inter-regional morphometric similarity. Regional MSN patterns were linked to Allen Human Brain Atlas using Spearman correlations with spin tests and a multi-K stability screen. Whole-blood RNA-seq (n = 199) was integrated with MSN features via sparse partial least squares-canonical correlation (sPLS-C), with key blood analyses repeated after leukocyte-composition adjustment. Gene Ontology over-representation and MAGMA gene-level analyses provided pathway context. HA showed greater MSN integration than LA, particularly within default-mode and somatomotor networks. MSN maps were negatively correlated with dopamine-transporter and kappa-opioid-receptor densities. Imaging-derived gene associations were enriched for regulation of Toll-like-receptor-3 signaling. In blood, sPLS-C revealed coupling between MSN features and a transcriptomic signature enriched for T-cell activation/differentiation and lymphocyte-apoptosis pathways. After composition adjustment, the pre-specified blood signature did not differ between HA and LA, indicating that between-group differences were largely composition-driven. As supportive genetic context, over-representation on MAGMA FDR-significant genes suggested protocadherin-mediated homophilic adhesion. Peripheral immune-redox pathway enrichment aligns with anhedonia-related cortical network alterations, whereas between-group blood differences are chiefly composition-driven. Adjusting for blood-cell composition is essential, this multimodal framework nominates immune-modulatory/redox targets and synaptic-adhesion biology for precision stratification and intervention.