Epidemiological and transcriptome data identify association between iron overload and metabolic dysfunction-associated steatotic liver disease and hepatic fibrosis.

• Iron overload links to metabolic dysfunction-associated steatotic liver disease. • Iron overload links to hepatic fibrosis. • Nonlinear associations seen in serum ferritin with controlled attenuation parameter. The primary objective of this study was to examine the association between iron overload (IO), metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatic fibrosis. We hypothesized that there is a significant association. Data from the NHANES (2017-2020) were analyzed to explore IO's impact on MASLD and hepatic fibrosis in U.S. adults. We assessed serum ferritin, controlled attenuation parameter (CAP), liver stiffness measurement (LSM), and various covariates. Gene expression data were sourced from the FerrDb V2 and GEO databases. Differential gene expression analysis, Protein-Protein Interaction (PPI) Network construction, and Gene Ontology (GO) and KEGG pathway enrichment analyses were performed. The study verified the link between MASLD, hepatic fibrosis, and iron overload hub genes. This study of 5927 participants, averaging 46.78 years of age, revealed significant correlations between serum ferritin and CAP, LSM, after adjusting for covariates. Threshold effect analysis indicated nonlinear associations between serum ferritin and CAP, LSM, with distinct patterns observed by age and gender. Moreover, the area under the ROC curve for serum ferritin with MASLD and hepatic fibrosis was 0.8272 and 0.8376, respectively, demonstrating its performance in assessing these conditions. Additionally, molecular analyses identified potential hub genes associated with iron overload and MASLD, and hepatic fibrosis, revealing the underlying mechanisms. Our study findings reveal an association between iron overload, MASLD, and hepatic fibrosis. Additionally, the hub genes may be implicated in iron overload and subsequently contribute to the progression of MASLD and hepatic fibrosis. These findings support precision nutrition strategies. The study analyzed data from 5,927 NHANES participants to reveal an association between iron overload, MASLD, and liver fibrosis. It showed significant correlations between serum ferritin and CAP, LSM, after adjusting for covariates. Additionally, molecular analyses identified the hub genes linked to iron overload, which may exacerbate MAFLD and hepatic fibrosis. CAP, controlled attenuation parameter; LSM, liver stiffness measurement; NHANES, nutrition examination survey; MASLD, metabolic dysfunction-associated steatotic liver disease. [Display omitted] [ABSTRACT FROM AUTHOR]