Iron metabolism in the human body encompasses several processes, including absorption, transport, utilization, loss, circulation, regulation, and storage. Maintaining Iron homeostasis is crucial to ensure adequate iron for essential biological functions while preventing toxicity from excess iron (Boccio et al., 2003). The oxidation state of iron significantly influences its absorption in the gastrointestinal tract, requiring it to be in the ferrous form (Fe2+) or bound to transporters for absorption. Dietary ferric iron (Fe3+) must be reduced to ferrous iron before uptake through divalent metal transporter 1 (DMT1) into intestinal epithelial cells. In contrast, If haem iron can be absorbed directly absorbed via haem carrier protein 1(HCP1) (Cheli et al., 2018). Upon absorption into intestinal epithelial cells, a portion of iron is stored as ferritin, while the remaining iron is transported into the circulation through ferroportin, located on the basolateral membrane. During this process, iron is reoxidized to its ferric form with the assistance of ferroportin auxiliary proteins, enabling it to bind to transferrin in the bloodstream. This binding facilitates the transport of iron to target organs for its biological roles. Hepcidin and transferrin are pivotal regulators of iron transport from cells to systemic circulation. Hepcidin, synthesized by the liver, is upregulated in response to increased iron levels, such as elevated iron stores and serum iron levels, as well as during infection and chronic inflammation, thereby playing a crucial role in maintaining iron homeostasis. Elevated hepcidin levels interact directly with membrane-bound iron transport protein (FPN), facilitating internalization and subsequent degradation. This process ultimately inhibits the efflux of iron into the bloodstream, thereby reducing circulating iron levels and contributing to iron homeostasis regulation (Nemeth and Ganz, 2021). Iron regulatory proteins (IRPs) bind to iron responsive elements (IREs), which are sequences found in mRNAs that encode iron-related genes. This binding controls the expression of these genes, including hypoxia inducible factor 2α (HIF2α) and transferrin receptor 1 (TfR1). Through this IRP/IRE posttranscriptional regulatory system, the cellular iron storage and homeostasis are effectively managed, ensuring appropriate iron levels for various cellular functions (Khan and Sharma, 2023; Sanchez et al., 2006). Iron is transported through the bloodstream by binding to transferrin, which delivers it to target organs. At these sites, iron binds to transferrin receptors on the cell surface and is internalized via clathrin-dependent endocytosis. Iron was delivered to different parts of the cell including the mitochondria by proteins poly (rC)-binding proteins 1 and 2 (PCBP1 and PCBP2) (Frey et al., 2014; Ryu et al., 2017). Mitoferrin 1 imports iron from intermembrane space to mitochondrial matrix for the synthesis of Fe S clusters. Once inside the cell, iron dissociates from transferrin and is reduced back to its ferrous form (Fe2+). The ferrous iron is then transported into the cytoplasm by DMT1 and can either be utilized in the mitochondria for various biochemical processes or stored as ferritin for future use (Barra et al., 2024; Gao et al., 2019).

High concentrations of iron are associated with carcinogenesis, a finding supported by epidemiological studies. In cancer cells, iron homeostasis is disrupted, resulting in elevated intracellular iron levels. Cancer cells, characterized by their rapid proliferation and heightened energy metabolism, exhibit a substantially increased demand for iron (Marques et al., 2014). To accommodate this demand, these cells predominantly store iron in the form of ferritin, consisting of both ferritin light chain (FTL) and heavy chain (FTH). Additionally, cancer cells exhibit a significant increase in the labile iron pool (LIP), which further contributes to their iron dependency. Iron uptake from the microenvironment is predominantly facilitated by the overexpression of TfR1 on the cell surface. This increased expression of TfR1 is crucial in enhancing cancer cell proliferation and invasion, making it an important target for the development of therapeutic strategies in cancer treatment. By focusing on TfR1, researchers aim to disrupt the iron acquisition pathway essential for tumor growth, presenting a promising avenue for effective cancer therapies. The Increased expression of import proteins, such as DMT1 and TFR1, has been demonstrated in colorectal cancer, leading to elevated intracellular iron. The STEAP family of proteins, which are involved in iron uptake and reduction within endosome, are also high expressed in various tumors, including glioma, prostate, pancreatic, and breast cancer (Rocha, 2021; Gomes et al., 2012; Chen et al., 2021). This elevated expression highlights the importance of the STEAP proteins in tumor iron metabolism and their potential as targets for therapeutic interventions in these cancers. Tumor cells were characterised of rapid self-renewal, therefore higher levels of nutrition were required compared to normal cells. Mitochondria was important organelles in process of energy synthesis. Iron plays an important role in mitochondrial enzyme synthesis. Excess iron was delivered to different parts of the cell including the mitochondria by PCBP1 and PCBP2. Mitoferrin 1 imports iron from intermembrane space to mitochondrial matrix for high concentration of Fe S clusters (Chung et al., 2014). Excess iron in mitochondria is also stored in ferritin (Levi and Arosio, 2004). Iron efflux is controlled by FPN, which is regulated by hepcidin. In many cancer cells, the low expression of FPN induces an increase level of intracellular iron (Lehmann et al., 2023). This is further compounded by the high expression of Hepcidin, which suppresses FPN and reduces iron export. Contrary to this, most cancer types exhibit high expression of iron import genes and low expression of iron export and storage genes, leading to an accumulation of iron within the cells. This dysregulation in iron homeostasis contributes to cancer cell proliferation and survival (Roth et al., 2019).

Iron is essential for DNA synthesis, repair, and cellular proliferation, which results in increased in iron uptake and elevated intracellular iron concentrations. Intracellular iron consists of components like ferritin heavy chain (FTH), ferritin light chain (FTL), and labile iron pool (LIP). The transferrin receptor, a membrane protein that binds transferrin, facilitates this high iron concentration typically observed in cancer cells (Jia et al., 2024; Rosager et al., 2017). TFRC is highly expressed in MXR-resistant cells, whereas its concentration is low in drug-resistant patients (Yu et al., 2024). To explore the relationship between iron metabolism and chemoresistance, studies on doxorubicin-resistant and cisplatin-resistant MCF-7 cell lines have shown elevated expression of TFRC1 and iron-regulating genes. Iron chelation leads to decreased levels of cycline A, B and D, resulting in G1/S phase arrest and inducing cell apoptosis (Kulp et al., 1996). Depletion iron disrupts the iron metabolism in cancer cells, which can help reduce drug resistance. The LIP is crucial for the proliferation of cancer cells, and iron chelators can effectively bind to the free iron within this pool, thereby inhibiting cell growth and proliferation. This strategy not only hampers the metabolic processes essential for cancer cell survival but also enhances the effectiveness of chemotherapeutic agents by overcoming resistance mechanisms. Iron chelator (DFO and DFX) enhance chemotherapy sensitivity (Wang et al., 2019; Liu et al., 2022). While High intracellular iron concentrations support the growth and proliferation of malignant cells, iron chelating agents inhibit tumor growth by depleting intracellular iron. Previous studies have demonstrated the anticancer effects of the iron chelator deferoxamine (DFO), which increases the chemotherapy sensitivity of ovarian cancer by inducing apoptosis in tumor cells. These findings suggest that depleting iron within cells can mitigate chemotherapy resistance, highlighting the potential role of iron chelation in cancer treatment strategies.

The stemness of cancer stem cells (CSCs) is associated with elevated levels of ferritin, both FTH and FTL, capable of storing more than 4,000 iron atoms. High ferritin levels are particularly linked to breast CSCs, whereas knockdown of FTH disrupts the expression of the cytokine oncostatin M and impairs stemness. FPN regulates the export of excess intracellular iron, a process modulated by hepcidin (HAMP). In breast cancer, high expression of HAMP and an increased LIP are correlated with poor prognosis and an invasive phenotype, alongside downregulated FPN expression. Overall, CSCs maintain high iron concentrations by enhancing iron uptake, reducing iron export, and stabilizing LIP homeostasis, contributing to their malignancy and resistance characteristics (Arruda et al., 2020).

Post-transcriptional regulation of iron in cancer stem cells (CSCs) is primarily mediated by iron regulatory proteins 1 and 2 (IRP1 and IRP2), which are RNA-binding proteins that play a critical role in iron metabolism. In non-CSCs, the Lip is enhanced by the proliferation-associated gene c-Myc. IRP1 bind to IREs, modulating the expression of genes related to iron metabolism and CSCs characteristics. CSCs are characterized by increased iron influx and decreased iron efflux, resulting in elevated intracellular iron. High levels of heavy-chain ferritin (H-ferritin) and intracellular iron is closely associated with CSC features in cancer. Iron supplementation significantly contributes to the maintenance of stemness and promotes chemoresistance in CSCs. The elevated iron levels in CSCs are critical, as evidenced by the upregulation of TFRC and DMT1, which enhance iron uptake and intracellular levels, thereby facilitating growth and maintaining CSC stemness (Brown et al., 2019; Lee and Roh, 2023).

Nanomaterial-based therapeutic compound delivery system has been explored to enhance therapeutic specificity and minimize systemic toxicity through the design of targeted therapy strategies. TFRC, which are iron-binding proteins located on cell membrane, play a crucial role in transporting iron necessary for cell proliferation. There receptors are expressed at low levels in normal cells but are significantly upregulated in malignant cells, including those from prostate, breast, pancreatic, leukemia, colon, and lung cancers (Currie et al., 2023; Yang et al., 2022; Liu et al., 2023; Zhang et al., 2024). In cancer cells, increased iron uptake via transferrin receptors has been observed, with accumulating evidence indicating that TFR1 is implicated in tumorigenesis and progression. The association between TFR1 and cancer underscores its potential as a drug target for cancer therapy (Candelaria et al., 2021). There are two subtypes of TFR, TFR1 and TFR2. TFR1 is generally expressed on the surface of most cells, whereas TFR2 is predominantly expressed in liver cells. These receptors are membrane glycoproteins that facilitate iron uptake via transferrin-bound iron (Fe III). The Tf-TFR1 complex is internalized through endocytosis, after which Fe (III) dissociates from TF. Given the high expression of TFRC in tumor cells, specific ligands targeting TFRC have been utilized for surface modification of nanomaterials, thereby to enhance selectivity and accumulation, thereby improving therapeutic efficacy.

The conjugation of transferrin with anti-transferrin receptor peptides has been investigated to enable selective drug delivery for tumor therapy (Nogueira-Librelotto et al., 2017). This drug delivery system enhances cytotoxicity in both drug-sensitive and drug-resistant cells, thus addressing limitations associated with current cancer management strategies. Overall, targeted transferrin therapy, leveraging the iron metabolism of cancer cells, has significantly advanced nanoparticle research.

Nanocarriers incorporating iron chelating agents have been extensively investigated for their potential in cancer treatment. Chelators such as DFO, deferasirox (DFX), and Dp44mT have shown promise in inducing iron deficiency within tumor cells, thereby inhibiting their proliferation (Ibrahim and O'Sullivan, 2020). However, the therapeutic efficacy of these iron chelating agents is limited by their short half-lives. DFO exhibits a half-life of approximately 20 min, which results in minimal impact on the iron levels within tumor cells. Considering the non-specificity of iron chelating agents in cancer therapy, the incorporation of nanomaterials offers a promising strategy to extend the drug cycle duration of these agents, leading to more effective cancer treatment (Ibrahim and O'Sullivan, 2020). Nanoparticles were engineered to prolong circulation time, enhance clearance, improve biosafety, and increase cellular permeability. Given the role of iron in promoting cancer progression in pancreatic tumors, a nanomaterial based on iron chelation has been developed. Liposomal drug delivery systems have been explored for the encapsulation of YC-1, a known inhibitor that targets DFO, transferrin (TF), and hypoxia-inducible factor 1α (HIF-1α). Transferrin modified nanomaterials enhance the expression specificity of membrane protein TFRC (Figure 2). Additionally, the iron chelating agent DFO acts synergistically with YC-1 to treat cancer. Pancreatic cancer CSCs exhibit elevated iron levels, and this novel, effective combined delivery of an iron chelator and YC-1 significantly enhances the efficacy of chemotherapy for pancreatic cancer (Lang et al., 2019).

Iron supply contributes to the growth and proliferation of stem cells, and iron derivatives specifically target stem cells can induce cancer cell death. Nanoparticulate deferoxamine (Nano DFO) has been formulated into polyethylene glycol lipid nanocapsules (LNCs) to enhance therapeutic efficacy. LNCs offer improved bioavailability, biosafety and anticancer effects. Compared to conventional iron chelating agents, the nanostructured formulation of DFO exhibits superior anti-tumor activity both in vivo and in vitro. Despite its effectiveness, the DFO family is still limited by challenges such as rapid clearance, poor cellular permeability, and cytotoxicity. To address these limitations, researchers have developed novel DFO derivatives that target CSCs by conjugating DFO with caffeine, thus improving permeability and targeting efficiency (Li et al., 2019). The newly developed compound demonstrates excellent cellular permeability and safety in depleting intracellular iron. The new derivative, DFCAF, surpasses DFO in effectively targeting cellular iron concentrations. DFCAF inhibits the growth and invasiveness of CSCs by suppressing the expression of the TGF-β signaling pathway.

Ferroptosis is a distinctive form of cell death reliant on the presence of iron and reactive oxygen species (ROS) (Park and Chung, 2019). In recent years, nanomedicine has emerged as a promising strategy for the effective treatment of various cancers using engineered nanomaterial-based therapeutic reagents. Increasing research has highlighted the significant relationship between ferroptosis and nanomedicine. Due to their nanoscale size, engineered nanomaterials can passively target tumor tissues through enhanced permeability and retention (EPR) effects, facilitating cancer-specific therapy (Alphandery, 2022). In addition, iron-containing nanomaterials can enhance ROS accumulation following cellular uptake, ultimately resulting in cell death and achieving therapeutic effects. However, the ferroptosis inducer Solanine A presents challenges due to its poor water solubility and high toxicity in animal studies. Utilizing amphiphilic biodegradable ph-sensitive nanocarrier can mitigate the adverse pharmacological profiles associated with certain therapeutic agents (Hassannia et al., 2018). For instance, In a leukemia cell xenotransplantation model, the antitumor activity of the erastin analogue IKE was enhanced when delivered via polyethylene glycol-polylactic-coglycolic acid nanoparticles (Zhang et al., 2019). Additionally, in xenograft models, ultra-small silica nanoparticles have been shown to induce ferroptosis by increasing intracellular iron transfer and accumulation, thereby inhibiting tumor growth (Kim et al., 2016). Li et al. (2022) devised and developed engineered exosome that were endogenously modified with brain tumor-targeting peptides and combined with magnetic nanoparticles through antibody conjugation. This platform enabled the loading of siGPX4 and Brequinar (BQR), an DHODH inhibitor, on exosomal surfaces and mesoporous silicon, respectively. Furthermore, a mouse magnetic helmet constructed using 3D printing technology facilitated the effective induction of ferroptosis for treating brain gliomas. nevertheless, the long-term effects of nanoparticle applications on human health require careful evaluation.