Iron metabolism and arthritis: Exploring connections and therapeutic avenues

Abstract

Iron is indispensable for the viablility of nearly all living organisms, and it is imperative for cells, tissues, and organisms to acquire this essential metal sufficiently and maintain its metabolic stability for survival. Disruption of iron homeostasis can lead to the development of various diseases. There is a robust connection between iron metabolism and infection, immunity, inflammation, and aging, suggesting that disorders in iron metabolism may contribute to the pathogenesis of arthritis. Numerous studies have focused on the significant role of iron metabolism in the development of arthritis and its potential for targeted drug therapy. Targeting iron metabolism offers a promising approach for individualized treatment of arthritis. Therefore, this review aimed to investigate the mechanisms by which the body maintains iron metabolism and the impacts of iron and iron metabolism disorders on arthritis. Furthermore, this review aimed to identify potential therapeutic targets and active substances related to iron metabolism, which could provide promising research directions in this field.

Figure 1

The systemic iron metabolism and non-heme dietary iron circulation. (1) Fe³⁺ is reduced to Fe²⁺ by DCYTB on the apical membrane of enterocytes. (2) Fe²⁺ enters the enterocytes via DMT1. (3) Fe²⁺ absorbed by enterocytes can enter mitochondria, be stored in ferritin, or be released into the systemic circulation via FPN1 on the membrane. (4, 5) The released Fe²⁺ is first oxidized to Fe³⁺ by CP or HP, and then combined with TF to enter the bloodstream for circulation. (6) Most of the circulating TF is absorbed by erythroid precursors in the bone marrow for erythrocyte production, and the rest is distributed to other tissues or organs that require iron. (7) Diferric TF binds to TFR1 and is internalized into the cell (using hepatocytes as an example) via endocytosis. (8) Within the endosome, the acidic environment causes TF to release Fe³⁺, which is then reduced to Fe²⁺ by STEAP3. (9) Fe²⁺ is released into the cytoplasm through DMT1 from the endosome. (10) Fe²⁺ iron in the cytoplasm can enter mitochondria for heme synthesis or be stored in ferritin. Enterocytes can uptake heme iron via HCP1 or HRG1. The heme iron entering the cytoplasm can be catabolized by HMOX1 to prevent toxicity. Then it may undergo the same transportation as Fe³⁺. The spleen is the main site for the recycling and reuse of iron in erythrocytes. Macrophages are responsible for recovering most of the iron from aged or damaged erythrocytes, effectively reusing the iron present in hemoglobin. Fe²⁺ catabolized by HMOX1 can be stored in ferritin or transported out of cells by FPN1 for further use. CD: Cluster of differentiation; CP: Ceruloplasmin; DCYTB: Divalent iron by duodenal cytochrome b; DMT1: Divalent metal transporter 1; FPN1: Ferroportin; HCP1: Heme carrier protein 1; HMOX1: Heme oxygenase 1; HP: Hephaestin; HRG1: Heme responsive gene-1; SLC39A14: Solute carrier family 39 member 14; STEAP3: Six-transmembrane epithelial antigen of the prostate 3; TF: Transferrin; TFR1: Transferrin receptor 1.

Figure 2

The molecular mechanism of reduced sensitivity to ferroptosis in RA-FLS. Ferroptosis is mainly caused by iron-dependent lipid peroxidation. GPX4 is a crucial factor that inhibits ferroptosis. Decreasing the accumulation of LIP, activating of GPX4 or related signaling pathways can suppress lipid peroxidation production and prevent ferroptosis. RSL3 is a known ferroptosis inducer. The data cut-off date for the analysis was February 1, 2024. 4E-BP1: 4E binding protein 1; AKT: Protein kinase B; FLS: Fibroblast-like synoviocyte; FTH1: Ferritin heavy polypeptide 1; GPX4: Glutathione peroxidase 4; GSH: Glutathione; HIF-1α: Hypoxia-inducible factor-1 alpha; LIP: Labile iron pool; mTOR: Mammalian target of rapamycin; NCOA4: Nuclear receptor coactivator 4; PI3K: Phosphatidylinositol 3 kinase; RA: Rheumatoid arthritis; SAM: S-adenosylmethionine; SCD-1: Stearoyl-CoA desaturase 1; SLC3A2: Solute carrier family 3 member 2; SLC7A11: Solute carrier family 7 member 11; SREBP1: Sterol-regulatory element binding protein 1; TNF: Tumor necrosis factor.

Figure 3

The molecular mechanism of ferroptosis exacerbating OA and potential therapeutic targets. Ferroptosis of articular chondrocytes is associated with the pathogenesis of OA. The pathways and networks through which ferroptosis regulates the progression of OA can be divided into four basic categories, specifically amino acid metabolism (blue background section), lipid metabolism (green background section), iron metabolism (red background section), and others (yellow background section). The red font indicates potential therapeutic drugs or reagents. The data cut-off date for the analysis was February 1, 2024. AMPK: Adenosine 5′-monophosphate-activated protein kinase; CX43: Connexin 43; DFO: Deferoxamine; DMT1: Divalent metal transporter 1; FOXO3: Forkhead box O3; FPN1: Ferroportin; GPX4: Glutathione peroxidase 4; GSH: Glutathione; HIF-1α: Hypoxia-inducible factor-1 alpha; HIF-2α: Hypoxia-inducible factor-2 alpha; HMOX1: Heme oxygenase 1; HSPA5: Heat shock protein family a member 5; JNK: C-Jun N-terminal kinase; LIP: Labile iron pool; MAPK: Mitogen-activated protein kinase; NCOA4: Nuclear receptor coactivator 4; NF-κB: Nuclear factor kappa B; NRF2: Nuclear factor erythroid 2-related factor 2; OA: Osteoarthritis; SCP2: Sterol carrier protein 2; SIRT1: Silent mating type information regulation 2 homolog-1; SLC2A1: Solute carrier family 2 member 1; SLC3A2: Solute carrier family 3 member 2; SLC7A11: Solute carrier family 7 member 11; SND1: Staphylococcal nuclease domain containing 1; SREBF2: Sterol regulatory element binding transcription factor 2; STEAP3: Six-transmembrane epithelial antigen of the prostate 3; TF: Transferrin; TF3: Theaflavin-3,3′-digallate; TFR1: Transferrin receptor 1; TGF-β1: Transforming growth factor-beta 1; TRPV1: Transient receptor potential vanilloid 1; YAP1: Yes-associated protein 1.