Abstract
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease globally, with significant liver fibrosis (SLF) determining clinical outcomes. Although complement activation is involved in MASLD pathogenesis, the clinical significance of circulating complement proteins (C1q, C3, C4, total activity) in aging populations remains unclear. This cross-sectional study aimed to evaluate the association between serum complement levels and MASLD/SLF in middle-aged and elderly adults. METHODS: We recruited 266 consecutive MASLD patients (age ≥ 45) and 150 age- and sex-matched healthy controls from Huadong Hospital. Multivariate logistic regression identified independent predictors of MASLD and SLF. Nonlinear relationships were assessed using restricted cubic splines. Spearman's correlation and mediation analyses explored clinical associations, while ROC curves evaluated diagnostic performance against established non-invasive indices. RESULTS: MASLD patients showed significantly higher levels of C1q, C3, C4, and total complement activity than controls (P < 0.05). After multivariate adjustment, C3 was independently associated with MASLD (OR = 1.04 per mg/dL, 95% CI: 1.02-1.06; P < 0.001). A nonlinear, inverted U-shaped relationship was observed between C3 and MASLD risk (P = 0.015), with peak risk at 143 mg/dL (OR = 2.53). C3 demonstrated high diagnostic accuracy for MASLD (AUC = 0.80, 95% CI: 0.75-0.85), comparable to validated models. Although lower C3 and C4 were associated with SLF in univariate analysis, this was not sustained after adjustment. No significant association was found between complement levels and SLF. CONCLUSIONS: Serum C3 is a promising diagnostic biomarker for MASLD in middle-aged and elderly adults, showing a distinct nonlinear relationship and strong discriminative ability. However, complement levels were not independently associated with liver fibrosis in this population. These findings suggest a potential role for C3 in MASLD diagnosis, but the cross-sectional design precludes causal inference, and further longitudinal studies are needed to confirm its clinical utility and elucidate underlying mechanisms.