Inflammatory markers mediate the association between depression and all-cause mortality: Evidence from NHANES 2007–2018

• First systematic evaluation of inflammatory markers as mediators between depression and all-cause mortality. • RDW exhibits stronger mediating effects than WBC. • Emphasizes the clinical utility of routine hematological indices in psychiatric research. • Establishes a biological bridge between depression, systemic inflammation, physiological dysregulation, and mortality risk. • Policy and clinical implications: Supports inflammation monitoring in depression management. Depressive symptoms are linked to increased all-cause mortality, but the biological mechanisms remain unclear. This study investigated whether systemic inflammatory markers—white blood cell count (WBC) and red cell distribution width (RDW)—mediate the association between depression and mortality in U.S. adults. Data from 13,061 participants in the 2007–2018 National Health and Nutrition Examination Survey (NHANES) were analyzed. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9). Cox proportional hazards models examined the association between depressive symptoms and all-cause mortality. Mediation analyses evaluated indirect effects of WBC and RDW. In fully adjusted models, severe depressive symptoms (PHQ-9 ≥15) were associated with higher mortality risk (HR = 2.18; 95 % CI: 1.17–4.09; p < 0.001). Depression scores were positively correlated with WBC (β = 0.33) and RDW (β = 0.21). Elevated WBC and RDW levels independently predicted increased mortality (WBC HR = 1.37; RDW HR = 2.53). Mediation analyses indicated WBC and RDW explained 12.2 % and 30.8 % of the total effect of depression on mortality, respectively. Depressive symptoms are significantly associated with higher all-cause mortality, partially mediated by systemic inflammation. RDW, in particular, may reflect chronic inflammatory burden linked to depression. These findings highlight the value of monitoring inflammatory markers in depression management to mitigate long-term mortality risk.