Serum n-3 fatty acids and obesity-comorbid depression in US adults: an integrated epidemiology and network pharmacology study.

n-3 PUFA, DHA and EPA possess anti-inflammatory properties, yet their association with obesity-depression comorbidity remains unclear. This study investigated the association among USA adults and explored underlying mechanisms. We performed a cross-sectional analysis of 4,423 adults participating in the National Health and Nutrition Examination Survey 2003-2004 and 2011-2014. Serum fatty acids were quantified by gas chromatography. Obesity was defined using anthropometric criteria, and depression was assessed using the Patient Health Questionnaire-9 or antidepressant use. Multivariable logistic regression estimated odds ratio (OR) per sd increase in PUFA levels. Mechanistic explore through network pharmacology identified potential pathways, which were examined using correlation analyses with inflammatory indices. Higher n-3 PUFA levels were associated with lower odds of central obesity comorbid depression in females (OR: 0·82, 95 % CI: 0·69-0·96) and older adults (OR: 0·79, 95 % CI: 0·64-0·97). DHA was significantly associated with lower odds of central obesity (OR: 0·83, 95 % CI: 0·73-0·95), depressive symptoms (OR: 0·88, 95 % CI: 0·77-1·00) and their comorbidity (OR: 0·85, 95 % CI: 0·74-0·98), whereas no significant associations were found for EPA. Mechanistic exploration implicated DHA in TNF and IL-17 signalling pathways, supported by inverse correlations with monocyte:HDL ratio (r: -0·138, P < 0·001) and lymphocyte:HDL ratio (r: -0·108, P < 0·001). In conclusion, serum DHA is inversely associated with obesity-depression comorbidity, with potential involvement of anti-inflammatory pathways. These findings underscore the potential of DHA for the management of obesity comorbid depression and the need for further interventional trials.