Fig. 2

Schematic diagram of the relationship between iron metabolism disorder and obesity and related metabolic diseases. Hepcidin over-expression can induce iron deficiency, and hemojuvelin (HJV) can promote hepcidin expression through the BMP/SMAD signaling pathway. ① In obese individuals, adipose tissue can regulate expression of hepcidin and HJV through overproduction of pro-inflammatory adipokines including IL-6, TNF-α and leptin; meanwhile, it also directly expresses hepcidin and HJV at high levels, which contribute to iron deficiency in obese individuals. ② The role of iron overload and ferroptosis in nonalcoholic fatty liver disease (NAFLD). Nuclear receptor coactivator (NOCA)4 contributes to iron overload by translocating ferritin to lysosomes and increasing the expression of iron regulatory protein (IRP)2 and transferrin receptor (TfR). Lipid peroxidation of membrane phospholipids can be eliminated by parallel metabolic pathways, including the cyst(e)ine/GSH/GPX4 axis, as well as the ferroptosis inducer (RSL3). In addition, several ferroptosis inhibitors such as sodium selenite (GPX4 activator), deferoxamine (iron-chelating agent) and ferrostatin-1 (ferroptosis inhibitor) can alleviate the onset and progression of NAFLD. ③ Iron-mediated toxic effects in beta-cells. Iron-mediated beta-cell toxicity is mainly due to reactive oxygen species (ROS) accumulation through the Fenton reaction. Excess ROS causes mitochondrial damage, leading to defects in the synthesis and secretion of insulin. ROS also influences the activity of the PDX1, MafA and AMPK, critical transcription factors for the control of insulin gene expression. In turn, hyperglycemia increases heme oxygenase (HO)-1 gene expression, exacerbates iron overload, promotes oxidative stress and the development of T2DM. In addition, misfolding and aggregated deposition of human islet amyloid polypeptide (hIAPP) due to iron overload can also lead to oxidative stress through endoplasmic reticulum stress, mitochondrial damage and complex formation by binding to heme. Besides, iron overload can stimulate glucose uptake and fatty acid oxidation by activating AMPK phosphorylation in skeletal muscle and liver, leading to an increase in glucose tolerance. ④ The relationship between iron overload and cardiovascular disease. Accumulation of iron in the heart has been supposed to depend on the penetration of Fe²⁺ through the L-type voltage-dependent Ca²⁺ channel (LVDCC). Non-transferrin-bound iron (NTBI) promotes atherogenesis by leading to ROS production through the Fenton reaction and stimulating monocyte chemotactic protein (MCP)1-mediated monocyte aggregation. In addition, iron overload inhibits SIRT1 and glutathione peroxidase (GPX)4, contributing to ferroptosis in foam cells and thus leading to atherosclerosis. Moreover, mixed lineage kinase (MLK)3 and Beclin1 can induce ferroptosis in cardiomyocytes through JNK/p53, and by affecting the levels of NOCA4, SLC7A11 and GPX4, respectively.