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To the Editor: Vascular calcification (VC) is a prevalent pathological feature of cardiovascular and cerebrovascular diseases, with its underlying mechanism still unclear. This knowledge gap poses challenges for developing effective treatment strategies to prevent or reverse VC. Iron, an important element for maintaining cellular and systemic functions, has been found to be closely associated with calcium levels. This study aims to illustrate the impact and potential mechanism of iron metabolism in VC and provide novel perspectives for diagnosing and treating this condition. Vascular calcification: VC is a major risk factor for life-threatening cardiovascular diseases, occurring in various cardiovascular tissues, including blood vessels, myocardium, and heart valves, and is characterized by calcium phosphate deposition.[1] Based on its location, VC can be categorized into several types, including intimal calcification, medial calcification, adventitia calcification, calciphylaxis, and valve calcification. The mechanisms underlying VC are complex; the key mechanisms that have received more attention include: (1) Phenotypic transition of vascular smooth muscle cells (VSMCs) from contractile to osteogenic: VSMCs are the predominant cells involved in vascular and heart valve calcification, and they typically exhibit a contractile phenotype characterized by the expression of contractile proteins, such as alpha-smooth muscle actin (α-SMA), smooth muscle 22-α (SM-22α), and smooth muscle protein. During osteogenic transformation, the expression of the specific protein runt-related transcription factor 2 (RunX2) is upregulated in VSMCs, while the expression of the differentiation marker protein α-SMA is downregulated. These processes signify the onset of calcification. Additionally, endocytic osteogenic VSMCs secrete stromal vesicles that promote this osteogenic transition. (2) Apoptosis and autophagy: Apoptotic cells release calcium-loaded apoptotic bodies and deposit hydroxyapatite in the extracellular matrix (ECM), initiating the calcification process and eventually forming calcification foci. This deposition of calcium phosphate crystals further promotes apoptosis and accelerates the calcification process. Autophagy serves as an endogenous protective mechanism against VSMC calcification by preventing apoptosis. However, when autophagy fails to maintain cellular survival, apoptosis is triggered in VSMCs, leading to calcification. (3) MicroRNAs (miRNAs) regulation: MiRNAs play a crucial role in regulating VC by modulating processes, such as osteogenic transformation of VSMCs, intracellular calcium and phosphate homeostasis, and matrix vesicle release. Furthermore, miRNAs can target specific molecules to regulate calcification. Other important mechanisms of VC include matrix degradation and remodeling, dysregulation of calcification homeostasis, oxidative stress, and inflammation. Calcific diseases are also associated with abnormalities in various biological processes, including transcriptional regulation, endoplasmic reticulum stress, lipid and mineral metabolism, cellular senescence, and extracellular vesicle secretion. Iron metabolism: Iron is an essential element in maintaining normal cellular function in mammals, playing a vital role in various physiological processes,[2] including energy metabolism, oxygen transport, and DNA synthesis. Both iron deficiency and overload pose risks to cellular and systemic health, making it critical to maintain iron homeostasis. Systemic iron homeostasis is regulated by the hepcidin-recombinant ferroportin 1 (FPN1) axis. FPN1 is a transmembrane iron export protein that mediates intracellular iron efflux into the bloodstream to regulate serum iron levels. When FPN1 binds to hepcidin, it triggers self-degradation, reducing cellular iron efflux and increasing intracellular iron levels. Conversely, the dissociation of hepcidin from FPN1 restores cellular iron efflux, decreasing intracellular iron levels. Intracellular iron homeostasis is primarily regulated by the iron-regulated protein (IRP)-iron regulatory element (IRE) system. When IRP binds to IRE, intracellular iron levels increase by inhibiting the expression of iron storage and export molecules, such as ferritin and FPN. Conversely, when IRP and IRE dissociate, intracellular iron levels decrease. In summary, iron homeostasis is maintained by the intricate interplay of factors, including iron absorption, storage, and metabolism. Role of iron metabolism in VC: Iron levels are closely correlated with calcium content in cells and tissues, with iron playing a dual role in regulating calcification, either promoting or inhibiting it. Iron exerts a hypocalcemic effect and negatively regulates the onset and progression of VC. For example, ferric citrate can prevent calcium deposition and ECM remodeling, protecting cells from calcification by inhibiting the osteochondrogenic transformation of VSMCs, inducing autophagy, and inhibiting apoptosis. Notably, ferric citrate can also delay and reverse calcification by preventing high phosphorus-induced apoptosis, promoting autophagy, and reversing osteochondrogenesis in the ECM. Furthermore, iron can inhibit the calcification process by binding to and reducing phosphate levels in VSMCs and regulating exosomal miRNA levels to suppress VSMC osteoblastic transformation. Therefore, iron is effective in preventing and blocking calcification. Conversely, iron can also promote calcification through various pathways. Particularly, iron induces calcification by promoting lipid and protein oxidation, upregulating the expression of bone morphogenetic protein 2 (BMP2),[3] and triggering apoptosis. Furthermore, iron induces elevated serum and aortic tissue levels of hepcidin, degrading FPN1 and ultimately leading to aortic stiffness and collagen deposition-associated vascular remodeling. Moreover, iron causes hypercalcemia and hyperphosphatemia, resulting in calcium deposition in aortic tissue, which upregulates the expression of osteoblast differentiation factors, such as RunX2, BMP2, and receptor activator of nuclear factor kappa B ligand, while downregulating the expression of osteopontin, a key inhibitor of calcification.[4] These processes ultimately lead to the development of calcification. The dual regulatory effects of iron on VC described above may be attributed to differences in the direction and effect of various types or doses of iron preparations on the modulation of VC. Higher doses of iron may promote VC, while lower doses may produce an inhibitory effect. Additionally, the type of iron preparation may also modulate its effect on VC. For instance, ferric citrate hydrate and saccharated ferric oxide have been shown to decrease serum calcium levels and aortic calcium deposition, preventing or reversing calcification, whereas ferric dextrose does not have these effects. Treatment of VC based on iron metabolism: VC poses a significant global health concern due to its association with a wide range of diseases. Although VC is a progressive, modifiable, and preventable disease, its underlying mechanisms remain unclear, and no effective treatments currently exist for its prevention or reversal. However, given the regulatory effect of iron in VC, systemic control and regulation of iron levels present a promising novel approach for treating VC. Traditionally, oral iron supplementation is a simple and cost-effective approach to addressing iron deficiency. However, oral iron therapy is often challenged by poor patient adherence, gastrointestinal side effects, and suboptimal therapeutic outcomes. In contrast, intravenous iron therapy is more effective in patients who cannot tolerate or do not respond inadequately to oral iron therapy. The primary intravenous iron formulations currently used in clinical practice are iron sucrose (IS), ferric carboxymaltose (FCM), and ferric derisomaltose (FDI), which have been proven to be safe, effective, and associated with a low incidence of adverse events. Additionally, ferric citrate, ferric hydroxyl trifluoride, and ferric hydroxide have been used clinically to treat hyperphosphatemia, which portends the risk of VC. Compared with IS, FCM and FDI allow for rapid, single, high-dose iron supplementation, shortening the treatment duration, and reducing costs for patients. However, FDI releases lower levels of labile iron compared to FCM and rarely causes hypophosphatemia, making it the preferred choice for intravenous iron therapy. Notably, alternative therapies, such as lactoferrin, which can modulate iron channels and improve iron levels, show promise as novel treatment options for diseases associated with abnormal iron metabolism, such as VC. However, excessive iron supplementation can lead to iron overload, with risks of hypercalcemia and hyperphosphatemia, which in turn can lead to calcification. In such cases, iron chelators can help restore the body’s antioxidant activity and iron metabolism, preventing or reversing iron overload-induced VC.[5] In addition, targeting specific factors involved in iron metabolism may offer a potential therapeutic target for managing iron overload, offering promise for the treatment and prevention of iron overload-associated VC. In conclusion, iron has a dual regulatory effect on calcification, either promoting or inhibiting it [Supplementary Figure 1, https://links.lww.com/CM9/C722], depending on the type and dose of iron used. Intravenous iron is an effective and well-tolerated treatment for calcification-causing hyperphosphatemia and iron deficiency. However, blood iron levels should be closely monitored in patients receiving iron therapy to prevent iron overload and resulting VC. Consequently, an ongoing study into potential mechanism of VC is crucial to developing effective treatments, including iron-based therapies and iron metabolism inhibitors, which hold significant prospects for addressing this complex condition. Funding This work was funded by grants from the Tianjin Health Science and Technology Project (No. TJWJ2022QN069), Tianjin Key Medical Discipline Construction Project (No. TJYXZDXK-3-017B), and Tianjin Chest Hospital Scientific Research Fund (No. 2018XKZ10).