Evaluation of FGL1 as a hepatokine marker in iron deficiency

Fibrinogen-like protein 1 (FGL1) is a hepatokine that regulates hepcidin through antagonism of the bone morphogenetic protein (BMP) pathway. Although preclinical studies suggest a role for FGL1 in iron metabolism, its clinical behavior in human iron deficiency anemia (IDA) remains unclear. This study evaluates circulating FGL1 levels in IDA and examines its diagnostic performance and relationship with hematologic and biochemical markers.

This cross-sectional study included 112 participants: healthy controls (n = 46), primary IDA (n = 46), and patients with IDA associated with chronic disease (IDA+CD) (n = 20). Hematologic indices, iron parameters, and serum FGL1 were measured. Group comparisons, correlation analysis, receiver operating characteristic (ROC) curves, and principal component analysis (PCA) were applied to assess diagnostic performance and multivariate biomarker structure.

Serum FGL1 concentrations were significantly higher in primary IDA (median 411.2 ng/ml) and IDA+CD (median 292.99 ng/ml) than in healthy controls (median 212.49 ng/ml; p < 0.001). Fibrinogen-like protein 1 did not differ significantly between IDA and IDA+CD (p = 0.106). In primary IDA, FGL1 showed weak correlations with iron markers, whereas in IDA+CD it demonstrated moderate associations with hemoglobinization indices, particularly MCH (r = 0.49). Receiver operating curve analysis showed excellent discrimination between healthy individuals and primary IDA (AUC 0.865) and good discrimination between healthy individuals and all disease groups combined (AUC 0.830). Fibrinogen-like protein 1 performed poorly in distinguishing primary IDA from IDA+CD (AUC 0.357). Principal component analysis showed that FGL1 clustered with classical markers of iron-restricted erythropoiesis along PC1, separating controls from both IDA groups.

Fibrinogen-like protein 1 is markedly elevated in iron deficiency and aligns with the broader biochemical signature of iron-restricted erythropoiesis. Its strong ability to distinguish healthy individuals from those with iron deficiency suggests diagnostic potential, particularly when ferritin interpretation is limited.