TY  - JOUR
TI  - From spark to wildfire: how hyperferritinemia fans the flames of metabolic dysfunction-associated steatotic liver disease
AU  - Weiskirchen, Ralf
PY  - 2025
JO  - Exploration of Digestive Diseases
VL  - 4
SP  - 100599
DO  - 10.37349/edd.2025.100599
UR  - https://www.explorationpub.com/Journals/edd/Article/100599
AB  - Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a multisystem disorder in which iron acts as both a metabolic “spark” and an accelerant of liver injury. This integrates emerging evidence that iron-driven oxidative stress and low-grade inflammation are mutually reinforcing processes in metabolic liver disease. In this perspective article, epidemiological evidence, molecular insights, and emerging clinical data are integrated to clarify how hyperferritinemia, often dismissed as a mere inflammatory marker, maps onto genuine iron redistribution and overload in the metabolic liver. Physiological iron homeostasis and its disruption by adiposity-related inflammation, hyperinsulinemia, sex hormones, and common HFE variants, creating a labile catalytic iron pool that fuels Fenton chemistry in lipid-laden hepatocytes. Population studies and expert-panel criteria are summarized that define “metabolic hyperferritinemia” and stratify dysmetabolic iron accumulation into three magnetic resonance imaging (MRI)-based grades, each linked to stepwise increases in steatosis, fibrosis, and clinical events. Mechanistically, excess Fe2+ triggers lipid peroxidation, mitochondrial dysfunction, ferroptosis, Kupffer cell activation, endoplasmic reticulum stress, and hepatic stellate cell sensitization to TGF-β, thereby accelerating the transition from steatosis to steatohepatitis and fibrosis. Finally, the diagnostic algorithms, iron-modulating therapies (phlebotomy, hepcidin agonists, diet), and prospective data supporting ferritin-based triage in clinics are discussed. Collectively, the outlined evidence positions iron not only as a biomarker but also as a modifiable driver of MASLD progression, underscoring the need for randomized trials that test whether targeted iron reduction improves hard hepatic outcomes.
ER  -