Circulating STAT3 and SMAD1/SMAD4 with Hepcidin Levels Across β-Thalassemia Subtypes: A Cross-Sectional Study

Background/Objectives: The background of the research shows that β-thalassemia is a hemoglobinopathy which is characterized by ineffective erythropoiesis and iron overload and this is kept in balance by hepcidin hormone due to BMP/SMAD and JAK/STAT3 pathways. However, it is not known how exactly these signaling pathways are involved in iron metabolism disorders for different forms of β-thalassemia, therefore, the aim of the present research was to analyze circulating levels of hepcidin, STAT3, SMAD1 and SMAD4 in participants with β-thalassemia and evaluate their exploratory discriminatory potential. Methods: The methodology of the research includes a comparative cross-sectional study of 135 patients with β-thalassemia major, intermedia and minor, as well as healthy control individuals based on hemoglobinopathy typing with the high-performance liquid chromatography. The circulating hepcidin levels, SMAD1 and SMAD4 concentrations as well as plasma STAT3 levels were identified and measured by ELISA method. Statistical processing methods include one-way ANOVA, multinomial logistic regression and ROC curve analysis based on ten-fold cross-validation. Results: Hepcidin and SMAD1 levels showed heterogeneity among groups, whereas differences in STAT3 and SMAD4 were not statistically significant. In multinomial logistic regression, lower hepcidin was associated with β-thalassemia major and lower SMAD1 with β-thalassemia intermedia. ROC analysis showed moderate in-sample discrimination for hepcidin and stronger discrimination for SMAD1. Conclusions: Altered circulating hepcidin and SMAD1 patterns may reflect dysregulation of BMP-SMAD/hepcidin signaling across β-thalassemia subtypes. These findings are exploratory and require independent validation before clinical application.