<p>Endoplasmic reticulum stress (ERS) is prevalent in liver disorders such as iron overload and metabolic dysfunction–associated steatohepatitis (MASH). Endoplasmic reticulum to nucleus signaling 1 (ERN1) is activated in response to ERS, however, the diagnostic value of circulating ERN1 and hepcidin in ERS-related liver disorders remains unclear. This study was carried out to find out the diagnostic power of ERN1 and hepcidin in patients with iron overload condition and those diagnosed with MASH.</p><p>In this case–control study, thalassemia patients with iron overload, patients with MASH, and healthy individuals (<i>n</i> = 30/group) were enrolled. Circulating hepcidin and ERN1 were quantified by ELISA, and their gene expression was assessed by quantitative PCR (qPCR). Total cholesterol and triglyceride were significantly higher in the MASH group than in the iron-overload and control groups. Serum iron and ferritin were increased in the iron-overload group relative to MASH and controls. ALT and AST were substantially elevated in both MASH and iron-overload compared with controls. Serum hepcidin was markedly decreased (~ 90%) in iron-overload but moderately increased in MASH, whereas ERN1 concentration was significantly elevated in iron-overload and modestly increased in MASH. Changes in circulating proteins were consistent with corresponding alterations in ERN1 and hepcidin mRNA abundance.</p><p>In conclusion, dysregulation of ERN1 at protein and mRNA levels appears to be involved in the pathogenesis of steatohepatitis and iron-overload states. Circulating ERN1 may serve as a marker of ER stress with potential diagnostic relevance in these disorders, while hepcidin deficiency supports the diagnostic utility of this marker for iron overload.</p>