Iron Homeostasis and Liver Diseases.

Abstract

Iron is an essential micronutrient whose ability to cycle between ferric (Fe³⁺) and ferrous (Fe²⁺) states makes it crucial for physiological processes, including oxygen transport, DNA synthesis, and oxidative phosphorylation. However, because both deficiency and excess can cause severe pathology, precise regulation is critical. The liver plays a central role in systemic iron metabolism, and growing evidence identifies hepatic iron dyshomeostasis as a key catalyst in diverse liver disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD/MASH), alcoholic liver disease, liver fibrosis, and hepatocellular carcinoma (HCC). Hepatic iron accumulation promotes liver injury primarily through oxidative stress, mitochondrial dysfunction, and ferroptosis. In this review, we synthesize the multi-layered regulatory landscape of hepatic iron homeostasis, encompassing systemic coordination, cellular fine-tuning, and epigenetic modifications. We thoroughly dissect the pathogenic impact of iron overload and critically evaluate emerging therapeutic strategies aimed at restoring iron balance, such as hepcidin mimetics and ferroptosis modulators. Finally, we discuss current literature gaps-including preclinical model limitations, the lack of standardized non-invasive biomarkers, and drug delivery bottlenecks-providing a clear roadmap for future translational research in iron-related liver pathologies.