ObjectiveSomatic symptom disorder (SSD) is characterized by physical symptoms and associated functional impairments that are often comorbid with depression and anxiety disorders. In this study, we explored relationships between affective symptoms and the functional connectivity of the default mode network (DMN) in SSD patients, as well as the impact of peripheral inflammation. We employed mediation analyses to investigate the potential pathways between these factors. MethodsWe recruited a total of 119 individuals (74 unmedicated SSD patients and 45 healthy controls), who were subjected to comprehensive psychiatric and clinical evaluations, blood tests, and resting-state functional magnetic resonance imaging scanning. We assessed neuroimmune markers (interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), tryptophan, serotonin, and 5-hydroxyindoleacetic acid (5-HIAA)), clinical indicators of somatic symptoms, depression, anxiety, anger, alexithymia, and functional connectivity (FC) within the DMN regions. Data were analyzed using correlation and mediation analysis, with a focus on exploring potential relations between clinical symptoms, blood indices, and DMN FCs. ResultsPatients with SSD had higher clinical scores as well as IL-6 and TNF-α levels compared with those in the control group (P < 0.05). The SSD group exhibited lower FC strength between the left inferior parietal lobule and left prefrontal cortex (Pfalse discovery rate (FDR) < 0.05). Exploratory correlation analysis revealed that somatic symptom scores were positively correlated with affective symptom scores, negatively correlated with the FC strength between the intra prefrontal cortex regions, and correlated with levels of IL-6, TNF- α, and tryptophan (uncorrected P < 0.01). Mediation analysis showed that levels of anxiety and trait anger significantly mediated the relations between DMN FC strength and somatic symptoms. In addition, the DMN FC mediated the level of trait anger with respect to somatic symptoms (all PFDR < 0.05). The levels of depression and trait anger exhibited significant mediating effects as suppressors of the relations between the level of 5-HIAA and somatic symptom score (all PFDR < 0.05). Further, the level of 5-HIAA had a mediating effect as a suppressor on the relation between DMN FC and state anger. Meanwhile, the levels of hs-CRP and IL-6 had full mediating effects as suppressors when explaining the relations of DMN FC strengths with the level of depression (all PFDR < 0.05). The patterns of valid mediation pathways were different in the control group. ConclusionsAffective symptoms may indirectly mediate the associations between DMN connectivity, somatic symptoms, and neuroimmune markers. Inflammatory markers may also mediate the impact of DMN connectivity on affective symptoms. These results emphasize the importance of affective dysregulation in understanding the mechanisms of SSD and have potential implications for the development of tailored therapeutic approaches for SSD patients with affective symptoms. Furthermore, in SSD research using DMN FC or neuroimmune markers, considering and incorporating such mediating effects of affective symptoms suggests the possibility of more accurate prediction and explanation.