Focus on ferritin in clinical practice and biomedical applications

Focus on ferritin in clinical practice and biomedical applications | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 7 May 2025 V1 Latest version Share on Focus on ferritin in clinical practice and biomedical applications Authors : Weiming Song , Liming He , Xiaoyan Xie , Beikang Tang , Honghui Xie , Ying Cai , Shuangjiang Li 0009-0004-3392-8582 [email protected] , and Lanjie Lei Authors Info & Affiliations https://doi.org/10.22541/au.174660859.91442623/v1 559 views 296 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Ferritin has gained widespread acceptance in both clinical settings and biomedical engineering applications owing to its exceptional biological characteristics. Ferritin has excellent in vivo safety and dissociative self-assembly properties, and can be endowed with novel functions using chemical or biological modification methods to form function-specific ferritins. In addition, ferritin has a cage-like spatial structure, functional modifiability, and is mostly used in the study of drug delivery systems and imaging-agent encapsulation. This paper systematically describes the current research progress on ferritin in various diseases, mainly including hematological diseases, malignant tumors, metabolic diseases, infectious diseases, and autoimmune diseases, and evaluates and summarizes the strengths and limitations of ferritin in biochemical detection, bioimaging applications, and therapeutic delivery systems. Finally, the development of ferritin is summarized and prospected. Ferritin currently offers numerous benefits in disease diagnosis and drug development within the realms of biotherapy, immunotherapy, and vaccinations. It is hypothesized that subsequent investigation will elucidate and apply the broad potential of ferro-albumin extensively across various medical and biological domains. Focus on ferritin in clinical practice and biomedical applications Author names Weiming Song a, 1 , Liming He a, 1 , Xiaoyan Xie b , Beikang Tang c , Honghui Xie a , Ying Cai d , Shuangjiang Li a, * , Lanjie Lei e, * 1 These two authors made equal contributions to this study and share first authorship. Author affiliations a Department of Stomatology, Changsha Stomatological Hospital, Changsha 410000, China b Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha 410011, China c Department of Rheumatology and Immunology, the Second Xiangya Hospital of Central South University, Changsha 410011, China d Future Science and Technology City Branch, Hangzhou Stomatology Hospital, Hangzhou 310000, China e Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou 310015, China * Corresponding authors Shuangjiang Li a * , Email: [email protected] Lanjie Lei e, * , Email: [email protected] Abstract Ferritin has gained widespread acceptance in both clinical settings and biomedical engineering applications owing to its exceptional biological characteristics. Ferritin has excellent in vivo safety and dissociative self-assembly properties, and can be endowed with novel functions using chemical or biological modification methods to form function-specific ferritins. In addition, ferritin has a cage-like spatial structure, functional modifiability, and is mostly used in the study of drug delivery systems and imaging-agent encapsulation. This paper systematically describes the current research progress on ferritin in various diseases, mainly including hematological diseases, malignant tumors, metabolic diseases, infectious diseases, and autoimmune diseases, and evaluates and summarizes the strengths and limitations of ferritin in biochemical detection, bioimaging applications, and therapeutic delivery systems. Finally, the development of ferritin is summarized and prospected. Ferritin currently offers numerous benefits in disease diagnosis and drug development within the realms of biotherapy, immunotherapy, and vaccinations. It is hypothesized that subsequent investigation will elucidate and apply the broad potential of ferro-albumin extensively across various medical and biological domains. Keywords : ferritin, clinical practice, biomedical engineering, drug delivery, biomolecular imaging, vaccines, biochemical assays Introduction As medical care continues to develop, increasing numbers of diseases are being detected and cured, providing a healthy life for more people. Substantial breakthroughs have been achieved in cancer diagnosis and therapeutics in recent decades. However, because of the constrained efficacy of chemotherapeutic drugs and the emergence of multi-drug resistance, cancer remains the predominant cause of fatal illness globally [1,2] . Therapeutic approaches for cancer are intricately correlated with the specific neoplasm classification and progression stage of the cancer. Treatment modalities are typically based on surgical intervention, chemotherapeutic administration, radiation therapy, molecularly targeted treatments, hormonal manipulation, immunological strategies, and genetic interventions. At present, targeted therapy is recommended as a relatively safe treatment for malignant tumors. It is a systemic treatment modality that targets the genetic alterations within cancer cells that help them grow, divide, and spread. Essentially, at the cellular molecular level, corresponding targeted therapeutic drugs are designed for cancer-causing sites that have already been clearly identified, and by using carriers with certain specificity, the drugs or other active substances that kill tumor cells are selectively transported to the tumor sites to attack the cancer cells. Most targeted therapies treat cancer by interfering with specific proteins that promote tumor growth as well as systemic spread, and are delivered using small molecule drugs or monoclonal antibodies. Targeted drugs specifically inhibit cancer-causing genes in cancer patients, are easy to administer, and have relatively few toxic side effects. Recently, growing safety challenges and worries regarding the inconsistent and unpredictable behavior of traditional nanomedicines in vivo have highlighted the distinctive nanocage architecture of natural ferritin nanocages. Their superior safety characteristics and precisely predictable in vivo actions render ferritin-based formulations especially appealing for crafting nanomedical solutions. Nucleic acid drugs have highlighted the irreplaceable superiority of traditional drugs in tumor therapy by virtue of their clear therapeutic targets and long-lasting high efficiency. A class of protein-based molecular drugs, mainly ferritins, are used as gene drug carriers and are widely used in research owing to their natural tumor targeting. Seaman et al. [3] found that human heavy chain ferritin (HFn) recognizes a tumor marker molecule, transferrin receptor 1, and subsequently, reported the presence of ferritin cages on temperature-controlled small molecule drug channels. Thus, ferritin possesses excellent properties for a tumor-targeted drug carrier, including efficient small molecule drug loading and targeting therapeutics against tumor-associated diseases. Thus, highly biocompatible ferritin is a promising material for nucleic acid drug carriers. Here, we first introduce the structure, properties, characteristics, and preparation methods of ferritin, and then summarize its applications in disease diagnosis and treatment, drug delivery, biomolecular imaging, and biochemical detection. In addition, we summarize the applications of ferritin in tissue engineering and regenerative medicine. Finally, the current research status of ferritin is summarized and discussed, and future research directions, exploring its multifaceted applications, are envisaged. 2. Ferritin 2.1 Discovery of ferritin The initial identification of ferritin occurred in equine splenic tissue in 1937. Serum ferritin quantification, however, required the purification of ferritin, generation of anti-ferritin antibodies, and subsequent development of high-sensitivity immunoassay methodologies. In 1965, ferritin was isolated by Richter from a malignant tumor cell line, and its presence was discovered in a variety of tissues and bodily fluids. Lawson et al. [4] elucidated the crystallographic structure of ferritin. The first definitive demonstration of ferritin was accomplished by Addison et al. [5] in 1972 utilizing immunoradiometric analytical techniques. Also in 1972, Addison et al. effectively confirmed that ferritin could be reliably detected within human serum. To explore correlations between serum ferritin concentration and overall body iron reserves, they assessed these levels in the general population, individuals with iron deficiency, and those experiencing iron overload. Their findings indicated elevated ferritin levels in subjects suffering from iron excess and reduced levels in those with iron deficiency [6] . By 1975, Jacobs and Worwood [7] posited that serum ferritin determination could be a “useful and convenient method of assessing the status of iron stores”. 2.2 Morphological structure of ferritin and characterization of properties 2.2.1 Ferritin genes and supramolecular assembly The ferritin superfamily comprises three main groups: traditional ferritins (Ftn), bacterial ferritins with heme (Bfr), and DNA-associated proteins from starved cells (Dps). Ftn and Bfr each comprise 24 subunits, while Dps is more compact with only 12 subunits. Ftn distribution spans plants, bacteria, and animals, while Bfr and Dps are exclusively found in prokaryotic life forms. Phylogenetic network analyses using structural and sequence similarities have deduced that these subclasses share an ancestral lineage [8] . Moreover, recent discoveries have revealed a novel ferritin type, encapsulated ferritin [9] , in bacteria and archaeal species. The assembly mechanism of this variant has been elucidated through detailed mass spectrometric techniques [10] . Ferritin is composed of two distinct subunits: the light (L-ferritin) and heavy (H-ferritin) chains, with respective molecular masses of 19 and 21 kDa. They are encoded by the FTH1 and FTL genes situated on chromosomes 11q and 19q, exhibit approximately 55% sequence identity, and possess analogous three-dimensional structures. These structures include four helices, arranged in both parallel and antiparallel formations (designated A–D), along with a fifth, shorter E helix angled at 60° to the others. These subunits coalesce into an almost spherical entity, a nanocage, characterized by internal and external diameters measuring 8 and 12 nm, respectively. This structure incorporates six hydrophobic tetrad (C4) channels and eight narrower hydrophilic triad (C3) channels, which are each constructed from four E-helix monomers and function as conduits for iron ions [11] . This ferritin nanocage, which encapsulates the iron core protecting it from external elements, maintains stability over a broad pH range (pH 3–9). The self-assembly mechanism of ferritin has been elucidated using a basic model considering tetramers, hexamers, and dodecamers as the sole intermediate forms [12] . Sato et al. [13] demonstrated that Escherichia coli ferritin a undergoes dissociation into dimeric units under acidic conditions while preserving its inherent class II and III configurations, and subsequently reassembles into a ferritin molecule comprising 24 subunits upon pH elevation. Moreover, the rate of ferritin assembly demonstrates a positive correlation with ionic strength, indicating that predominantly repulsive electrostatic interactions among the assembled units significantly influence ferritin self-assembly kinetics [14] . This suggests that manipulation of pH and ionic strength can effectively trap small molecules within ferritin nanocages, thereby facilitating biotechnological uses like drug delivery. Additionally, Förster resonance energy transfer (FRET) can aid in clarifying the kinetics and mechanisms underlying ferritin self-assembly. The formation of heterodimeric H/L complexes proceeds with enhanced kinetic efficiency and a thermodynamic advantage compared to that of H/H homodimers, representing the initial phase in the hierarchical assembly process [14] . The preference for heterodimeric structures over homopolymers in structural ferritin is thus explained. Notably, ferritin multimers predominantly comprise heteropolymers formed by two different subunits, even when the concentration of one subunit is markedly lower. The relative proportions of the H/L subunits are further determined by the differential abundance and bioavailability of each subunit type within specific cellular microenvironments. Fig.1 The spontaneous self-assembly of ferritin. (a) The schematic representation illustrates the biphasic methodology employed for FTn-Ner synthesis via self-assembly followed by post-assembly modification. This entailed the formation of a homogenous FTn motif through the aggregation of 24 FTn subunits, which were originally expressed within Escherichia coli. Following purification, these FTn motifs underwent further integration to construct diverse FTN-NER structures, facilitated by the utilization of dual-arm PEG linkers. Reprinted from Ref. [15] with permission from Springer International Publishing. (b) Schematic representations of FHn obtained through alternative methodological approaches. FHn structures are generated either via the in vitro assembly of heterogeneous ferritin subunits through sequential disassembly-recombination protocols (left panel) or through direct intracellular self-assembly of heterogeneous ferritin subunits expressed within E. coli systems (right panel). Reprinted from Ref [16] with permission from Wiley. The typical microbial ferritin molecule (FTN) is a highly symmetrical, hollow (8 nm), spherical structure comprising 24 subunits with an outer diameter of ~12 nm, a ferric tetroxide-based iron core located in the center of the subunit shells, and thousands of ferric hydroxide molecules and hundreds of phosphate molecules in a non-homogeneous structure, with a molecular mass of 450 kD. In addition, three different types of ferritin molecular structures have been identified, including bacterial ferritin, encapsulin ferritin, and DNA-binding ferritin, and there are size differences between them. Although microbial and plant ferritins have the same subunit structure, mammalian ferritins are different, with heavy chain (H-type) subunits and light chain (L-type) subunits that are assembled in different ratios in different tissues to form complete ferritins. The DNA-binding ferritins found in Archaea and bacteria are the smallest type of ferritin, and have the function of normal iron ion oxidation and storage, and the ability to bind non-specifically to DNA. Encapsulins are the largest type of ferritin found in bacteria to date. Encapsulin subunits do not contain an iron oxidase center, and they can oxidize and store iron ions using loaded ferritin, which often contains additional ferritin-like proteins. At the atomic level, encapsulins have been subdivided into Mucor ferritin, Thermoanaerobacter nanoferritin, and virulence-like Thermoanaerobacter ferritin. Fig. 2 Structures of ferritin nanocages. (a) The spherical cage-like architecture comprising an internal iron core encapsulated within a protein shell, characterized by precise dimensional parameters including inner and outer diameters of 8 nm and 12 nm, respectively. (b) The four-helix bundle configuration representing the structural organization of an individual ferritin subunit. The structural elements are designated as follows: a, b, c, d: α-helices; e: short helical segments. (c) The tertiary structural arrangement of the human ferritin heavy chain exhibiting characteristic 4.3.2 symmetry elements. Reprinted from Ref. [17] with approval from Royal Society of Chemistry. The ferritin molecule possesses three chemically distinct active interfaces: the inner surface, outer surface, and inter-subunit interface, all of which can be chemically and genetically modified to achieve functional ferritin regulation. Chemical modification refers to the chemical coupling of functional small molecules, such as dye molecules and bursting agents, to specific ferritin amino acids, while genetic modification involves the targeted mutation, addition, or deletion of specific amino acids to alter the genetic sequence of ferritin. The coupling and modification of functional groups on the outer surface of ferritin can induce properties such as luminescence and imaging, the inner surface is mainly used as a nanoreactor to synthesize inorganic nanomaterials or for reactive nutrient molecule encapsulation, and the inter-subunit interfaces can be used to regulate the dissociative recombination of ferritin molecules and design novel caged proteins. The modification and transformation of these three active interfaces can expand the application space of ferritin molecules. 2.2.2 Iron loading in ferritin and iron oxidase activity The nanocage architecture of the multimeric protein Ferritin can encapsulate approximately 4,500–5,000 iron atoms [18,19] . Animal ferritin includes two distinct subunits, each serving unique roles. The H-ferritin subunit exhibits ferro-oxidase activity, enabled by a binuclear iron-binding site [20] , whereas the L-ferritin subunit, lacking such a site, primarily engages in iron storage and mineralization within the ferritin core. Research has elucidated the iron oxidation and ferritin loading processes, including detailed in vitro studies of reaction kinetics [21] . Upon oxidation of Fe 2+ to Fe 3+ at the ferric oxidase site, the ion swiftly migrates to the nucleation center on the L-ferritin subunit, facilitating entry of another Fe 2+ ion into the oxidase site. This interaction within the heteropolymer increases the oxidase activity of the H-ferritin subunit through a synergistic mechanism, accelerating iron oxidation and nucleation in the H/L-heteropolymer [22] . Consequently, the H-subunit is essential for the efficient conversion of Fe 2+ to Fe 3+ , while the L-subunit is vital in scavenging and storing iron, supporting its mineralization [23] . Although a ferritin nanocage comprising only L-subunits can convert Fe 2+ to Fe 3+ , the reaction rate is significantly slower. Upon reaching the catalytic site, Fe 2+ ions undergo oxidation via molecular oxygen (O 2 ) or hydrogen peroxide (H 2 O 2 ) [24] , forming various ferritin oxide minerals such as hydrotalcite (5Fe 2 O 3 -9H 2 O), magnetite (Fe 3 O 4 ), maghemite (γ-Fe 2 O 3 ), or hematite (α-Fe 2 O 3 ), depending on the biological environment and iron content of the ferritin [25,26] . The mechanism of iron oxidation within the ferritin core involves an Fe(III)-O-Fe(III) complex that is maintained at the iron oxidase center until displacement by Fe 2+ occurs [27] . This was elucidated by a recent investigation employing differential pulse voltammetry, which identified sequential disintegration within this mechanism. Historically, research has demonstrated involvement of only the C3 channel in iron incorporation and oxidation processes. However, recent findings indicate that the C4 channel also plays an active role [28] . As iron is incorporated into ferritin, the mineral core undergoes transformation, forming various structures, either solid or hollow, which extend along the ferritin shell [18] . Understanding the contributions of these diverse iron core structures to ferritin’s cellular function remains a pivotal research area. C3 channels serve as the principal route for ferric ions entering ferritin nanocages. Investigations using molecular dynamics have pinpointed the Fe 2+ ion binding sites within these C3 channels [29] , where multiple Fe 2+ ions can bind concurrently. As an additional ion approaches the channel entrance, the deepest ion is expelled from its internal binding site, migrating towards the ferric oxidase location. The extent of iron deposition within ferritin may be influenced by the fluctuating iron concentrations proximate to the ferritin complex. An increased labile iron pool presence could alter the reaction kinetics, thereby enhancing iron accumulation within ferritin. In research on Rana catesbeiana H-ferritin, two Glu residues were identified forming a secondary Fe 2+ binding site. This site links the exit of the ferritin ion channel directly to the catalytic or nucleation site utilized by iron oxidase [30] . Comparative analysis of Fe 2+ , Mg 2+ , and Zn 2+ ion movement revealed that the E130 residue in the C3 channel likely influences metal selectivity by impacting ion diffusion kinetics. Furthermore, the carboxylate of residue D127 is crucial in defining both the dimensions and the electrostatic characteristics of the ion channel near its internal outlet [31] . Notably, a mutation like D127E within the ferritin chain sequence can profoundly alter iron transport through the channel by modifying these electrostatic properties, markedly diminishing both ferritin’s enzymatic function and the development of an iron mineral core within the polymorph [32] . Iron in an unstable state may permeate ferritin structures through diffusion. In humans, specific chaperone proteins—human poly(rC)-binding proteins 1 and 2 (PCBP1 and PCBP2)—are implicated in facilitating the transfer to ferritin [33] . These proteins, which bind to both DNA and RNA, are preserved across mammalian species, prevalent in expression, and found in both the cytoplasmic lysate and the nucleus. Their cytoplasmic iron chaperone function makes them crucial for managing intracellular iron movement [34,35] . Notably, the presence of both PCBP1 and ferritin within the nucleus suggests that PCBP1 might also facilitate iron transfer into the nucleus and potentially into additional cellular compartments. Further investigations are essential to clarify these roles. Furthermore, PCBP1 establishes an iron chaperone complex with BolA family member 2 (BolA2) and glutathione, facilitating cytosolic [2Fe-2S] cluster formation on BolA2-Glrx3 (glutathione 3) [36] . Consequently, PCBP1 is recognized as crucial not only for iron sequestration but also for the generation of iron-sulfur clusters, which are essential to the functioning of numerous cellular proteins. To date, PCBP1 remains the sole identified iron chaperone that interacts with ferritin structures. However, additional chaperones that could participate in the loading or extraction of iron from ferritin warrant exploration. 2.3 Distribution and mode of ferritin Ferritin is ubiquitously distributed throughout human tissues and organs. It functions as the principal protein involved in storing iron ions (mainly in the cytoplasm), which is the predominant form of physiological iron storage. The highest ferratin content exists in the spleen, liver, and bone marrow, with additional distributions documented in tissue serum and blood cells. Serum ferritin is characterized as one of the most iron-abundant proteins within the human body. The liver, spleen, red bone marrow, and intestinal mucosa serve as the primary repositories for iron reserves, collectively accounting for approximately 66% of the total bodily iron content. Alongside yeast systems, ferritin is extensively distributed in animals, higher plants, bacteria, fungi, and archaea, and has the functions of storing iron, regulating iron ion metabolism, maintaining iron homeostasis, and protecting cellular components. In mammalian systems, ferritin is detected in virtually all tissues, with particularly elevated concentrations in hepatic and splenic tissues. Ferritin localization encompasses both intracellular and extracellular environments. Intracellular ferritin is predominantly localized within the cytoplasm, nucleus, and mitochondria, whereas extracellular ferritin is detected in various biological fluids, including serum, synovial fluid, and cerebrospinal fluid. 2.4 Biological functions of ferritin Ferritin serves as an iron storage protein extensively distributed across diverse organisms. It has two main biological functions: first, to convert divalent iron ions into soluble, non-toxic, bioavailable trivalent iron forms and store them in the internal cavities of proteins to regulate iron metabolism homeostasis; and second, to function as a scavenger of ferrous ion-mediated free radicals, thereby shielding cellular components from oxidative damage. Natural ferritin comprises two parts, the protein shell and the internal iron core. The shell is constructed from 24 subunits, either identical or heterogeneous, arranged in a highly symmetrical configuration that results in a hollow cage-like structure. Conversely, the iron core consists of numerous iron hydroxide and phosphate molecules, which can be extracted through reduction reactions under anaerobic conditions to yield a deferritin shell with an accessible internal cavity [37,38] . The structural integrity of the ferritin cage is characterized by remarkable stability, exhibiting exceptional tolerance to acidic and alkaline conditions (pH 2.0–12.0) and thermal resistance (protein denaturation occurs at temperatures between 70–80 °C). The high-level structure of ferritin is mainly maintained by inter-subunit hydrogen bonding and hydrophobic interactions. Thus, the subunits can be dissociated and reassembled physicochemically, and its reversible dissociation and reorganization properties establish the foundation for employing ferritin nanocages as encapsulation vessels and delivery vehicles in various applications [39] . 2.5 Characterization of different sources of natural ferritin Ferritin subunits H and L coalesce in distinct proportions to construct aggregates of 24 units, structures whose organization is dictated by these specific ratios. Comparative analyses of liver and placental ferritin revealed substantial inter-organ variations in subunit composition [40] . Tissues rich in adiponectin, such as muscle and various brain tissues, typically exhibit enhanced metabolic activity and energy exchange. These tissues are susceptible to reactive oxygen species (ROS) generation, and commonly exhibit elevated H-ferritin levels, facilitating surplus iron mineralization. Research on H-ferritin-deficient mice demonstrated escalations in oxidative stress and disturbances in other iron-regulatory proteins while their brain iron levels remained normal [41] . Similarly, heart tissue, known for its high H-ferritin content, has been identified as iron-abundant [42] . In contrast, organs like the liver and spleen, pivotal in iron storage, display high concentrations of L-ferritin [43] . Studies on rats indicate inconsistent ferritin distributions within the liver, with accumulation predominantly in hepatocytes and reticuloendothelial cells [44] . This suggests that specialized liver zones participate in iron storage and that particular transcriptional programs govern H-ferritin expression [45] . L-ferritin and H-ferritin expression is controlled through both the transcriptional and post-transcriptional mechanisms within cardiac and hepatic tissues, with similar regulatory patterns potentially occurring in additional organs [46] . Investigations utilizing transgenic murine models, wherein H-ferritin expression was governed by a tetracycline-responsive promoter, have demonstrated that elevated H-ferritin concentrations correlate with iron levels and induce an iron-depleted phenotype. These findings suggest that H-ferritin plays a beneficial role in maintaining iron homeostasis across diverse tissues [47] . The observed molecular interaction between nuclear receptor coactivator 4 (NCOA4) and H-ferritin [48] during ferritin phagocytosis implies that NCOA4 preferentially targets ferritin aggregates rich in H-ferritin for degradation, rather than those predominated by L-ferritin. Consequently, the interplay between H-ferritin and NCOA4 likely influences iron release rates across different tissues and organs. 2.6 Structural modification of ferritin Because the relatively homogeneous size and shape of natural proteins limits their applications, scientists artificially designed and constructed novel ferritin nanocages. The interfaces between the four ferritin-molecule subunits are important for ferritin cage formation. The C3–C4 interface has the largest surface area, followed by the C2, C3, and C4 interfaces. Zhang Shengli et al. [49,50] converted the 24-aggregate ferritin into 16-aggregate and 48-aggregate cages by inserting or deleting amino acids at key positions of the C3–C4 interface. The 16-aggregate ferritin comprised two similar 8-aggregates linked together by hydrophobic interactions, forming an oblate, hollow structure. The 48-aggregate ferritin had an enlarged outer diameter of 17 nm, with an inner cavity capacity unstable under solution conditions, being converted into a bowl-shaped 8-aggregate ferritin with a diameter of ~10 nm. Using this bowl-shaped 8-polymer ferritin as a template, Zang Jiachen et al. [51] designed an intra-chain disulfide bond and inter-chain disulfide bond, successfully converted it into three novel cage proteins, a cage 24-polymer (outer diameter 12 nm), ellipsoidal 16-polymer (long axis 10 nm, short axis 8 nm), and cage 48-polymer (outer diameter 17 nm). In contrast, when the C3–C4 interface of ferritin is completely eliminated, the 49 residues at the carboxyl terminus of the ferritin subunit are deleted, converting ferritin into an 8-aggregate nanocyclic structure [52] ; the inner wall comprises only B-helices, while the outer wall comprises A-helices, C-helices, and BC-loops with a height, inner diameter, and outer diameter of 5.1, 3.2, and 7 nm, respectively. In addition to re-designing the interfacial forces to obtain novel ferritins with different sizes and shapes, studies regulating the intramolecular assembly of ferritin were also successful. Huard et al. [53] modified the ferritin C2 interface to allow ferritin self-assembly to be controlled by the binding of divalent copper ions. Gu Chunkai et al. [54] successfully prepared a new four-polymer ferritin by inserting a histidine domain into the C4 interface of the iron storage protein. Transition metal ions, such as nickel, copper, and zinc, induced the self-assembly of this ferritin into a 24-polymer cage protein under near-neutral conditions, and this protein could be dissociated into the four-polymer by adding chelating agent, providing a good application model for embedding biologically active substances into ferritin under neutral conditions. 3. Methods of ferritin preparation and modification 3.1 Ferritin preparation 3.1.1 Physical incubation This method is mostly used for the encapsulation of small molecule drugs through the hydrophobic and hydrophilic channels in ferritin’s structure. The architectural configuration of ferritin nanocages is characterized by eight hydrophilic and six hydrophobic channels, providing effective paths for metal ions and various small molecules to enter the structure. Therefore, ferritin can be directly mixed with the drug molecules to be encapsulated and then incubated, making use of the cavities to encapsulate the drugs. However, the efficiency of this encapsulation method is greatly reduced for drugs with high molecular weight. Copper ions can be used to allow ferritin to encapsulate adriamycin via physical incubation. The copper ions and adriamycin are first incubated to form complexes that can travel efficiently through the hydrophilic channels of ferritin, so that the ferritin cage structure can encapsulate the drug. In contrast hydrophobic drugs, such as gefitinib and tyrosine kinase inhibitors, can use the hydrophobic channels to complete drug encapsulation. The incubation method is also applicable to the genetically engineered constructs of ferritin drug carriers for the co-delivery of pro-hydrophobic drugs. The hydrophobic peptide-hydrophilic peptide-RGD peptide functional motif is replaced with the fifth helix of the human heavy chain ferritin subunit so that the peptide functional motif is on the outer surface of the ferritin. Through the hydrophilic drug channels of ferritin and the hydrophobic peptides on the outer cage surface, the hydrophilic drug epimedin and the hydrophobic drug camptothecin were loaded into the inner lumen and the outer surface of the cage-like structure of ferritin, respectively, when incubated for a certain amount of time. The disadvantages of this method, in addition to the inability to encapsulate macromolecular drugs, are that neither the drug loading capacity nor the encapsulation rate is high due to the limitations of the encapsulation mechanism. There is still much room for improvement. 3.1.2 PH-mediated depolymerization/reorganization methods This method is mostly used for the encapsulation of large molecules, and its basic principle is to use pH changes to induce depolymerization and reorganization of the ferritin cage structure, encapsulating the drugs in the process. This pH-dependent depolymerization and reorganization method has proven more effective for drug encapsulation than alternative approaches. It is crucial to identify the optimal pH, as various ferritin types demand specific pH ranges to undergo depolymerization and reconstitution. For instance, standard ferritin requires a pH 11 for depolymerization, while abnormal ferritin must be depolymerized at a pH <4. The disadvantages of this method are that too high or too low pH environment may permanently damage the structural properties of ferritin, decreasing drug encapsulation capacity and stability, that the transformation process is difficult, and that it is not applicable to pH-sensitive drugs. 3.1.3 Urea gradient method Ferritin is mixed with a urea solution, which denatures the ferritin to encapsulate the drug. The ferritin is stabilized and denatured in low and high concentrations of the denaturant, respectively. First, ferritin is mixed with a high-concentration urea solution to depolymerize it into subunits. Then, the therapeutic compound intended for encapsulation is introduced to the system and the urea solution concentration is decreased, gradually reducing the denaturation of the ferritin cage structure and encapsulating the drug. Depending on the urea concentration, the encapsulation method differs slightly. When the urea concentration is extremely high, the ferritin cage structure is completely depolymerized and the drug is encapsulated during its reorganization; when the urea concentration is controlled within a certain range, the cage structure is not completely depolymerized but its channels are widened by the urea solution, allowing more drugs or drugs with larger molecular weights to enter. This method has relatively low efficiency although the drug loading capacity is good. In the use of natural H-ferritin for adriamycin encapsulation, ferritin is mixed with high-concentration urea, rotated until complete depolymerization, and adriamycin is added. After incubation for a certain period, all free adriamycin is removed by gradient dialysis with adriamycin-containing urea buffer. The remaining adriamycin is encapsulated in the ferritin cage structure. 3.2 Methods of ferritin modification 3.2.1 Chemical modifications Different modifiers, such as antibodies, fluorescence, enzymes, polymers, etc., are attached to the surface of ferritin to overcome its deficiencies or to provide new functions. The use of antibodies to recognize specific antigens can mediate specific interactions between cells, and ferritins attached to antibodies have certain targeting effects. The earliest chemical modification of ferritin was to attach it to an antibody using a bifunctional reagent such as glutaraldehyde. Ferritin-labelled antibodies were used to interact with the antigen, and the high-density iron nuclei of ferritin were used as electron microscopic markers to detect antigen–antibody binding sites. Ferritin–antibody conjugates with an immunoreactivity as high as 92% were produced by Hainfeld et al., and Tang et al. attached anti-human plasma copper blue antibody to the surface of ferritin using a biotin-affinophile. Surface-conjugated anti-human plasma cuprocyanin antibody and ferritin containing iron nuclei were used as a peroxide mimetic enzyme for cuprocyanin detection in human plasma samples via a double-antibody sandwich enzyme-linked immunoassay (ELISA). It has been established that ferritin nanocages, characterized by exposed lysine and cysteine residues on their exterior, can be subjected to chemical modification processes, thereby enhancing their tumor-targeting capabilities. 3.2.2 Biological modifications Specific combinatorial sequences are added to ferritin gene sequences, which are transferred into bacteria via vectors and used to express novel ferritins with specific functions. Biological ferritin modification involves modification by recombinant technology with a high degree of specificity; a specific binding sequence is added to the ferritin gene sequence, it is transferred into bacteria through a suitable vector, and the bacteria is used to express a novel multifunctional ferritin with specific requirements. Almost any part of ferritin can be modified using recombinant gene technology. A peptide fragment hydrolysable by thrombin was fused to the N-terminus of the ferritin (Pf_Fn) subunit of hyperthermophilic bacteria, and the glycine located at the C-terminal end of the protein-shell was replaced with a cysteine for specific binding to the target molecule. Then, the surface of the ferritin was modified with biotin to bind the target ligand using chemical modifications. When thrombin cleaves the peptide, the target molecule bound at the C-terminus of ferritin is exposed, forming a multifunctional nanodelivery platform controlled by protease. A number of studies have genetically engineered specific peptides or fluorescent probes on the outer surface of ferritin for in vivo cellular imaging. For example, Lee et al. integrated green fluorescent protein (GFP) into the outer surface of human H-subunit ferritin through a glycine-rich peptide, which increased fluorescence intensity and stability, and then chemically modified and attached a DNA aptamer to the outer surface, which significantly enhanced the detection sensitivity. 4. Ferritin in clinical medical practice Different modification methods can form specific functional ferritins, and the results of biochemical assays can be used to monitor these ferritin levels and assist in the assessment of disease processes. Ferritin level tests (biochemical assays) have clinical value for monitoring and assessment, assisting in the diagnosis or evaluation of iron-deficiency anemia, neurological disorders, inflammatory state, chronic liver disease, iron overload, malignant tumors, metabolic syndrome, and other diseases. 4.1 Clinical significance of ferritin testing 4.1.1 Ferritin and iron deficiency In clinical settings, serum ferritin is predominantly utilized alongside other markers to assess patient iron levels. Among the array of laboratory assessments, serum ferritin is considered the most reliable parameter for diagnosing iron scarcity. While the definitive method involves iron-stained bone marrow biopsies, serum ferritin levels below 12 µg/L are strongly associated with depleted iron stores. Beyond iron shortage, only hypothyroidism and a lack of ascorbic acid are known to decrease serum ferritin levels, and these rarely obscure the clinical interpretation of ferritin data [55] . For accurate iron deficiency screening in clinical practice, setting a higher cutoff for ferritin, especially in patients without complicating factors such as infection or inflammation, is advised; a threshold of 40 µg/L could enhance diagnosis sensitivity. Research has demonstrated that 25% of female subjects with confirmed bone marrow iron deficiency maintained serum ferritin values exceeding 15 µg/L [56] . Serum ferritin levels are commonly measured to differentiate iron deficiency from anemia of chronic disease, particularly when the cause of anemia remains unidentified. As mentioned above, if the value is extremely low, the test is almost diagnostic of iron deficiency. However, in numerous instances, ferritin serves as a less definitive diagnostic marker, and additional testing is required due to alterations in iron regulation prompted by inflammatory responses [57] . In these scenarios, assessing soluble transferrin receptor (sTfR) serum levels might prove beneficial. These receptors are released by hematopoietic cells experiencing iron depletion, indicating the upregulation of transferrin receptors in response to iron scarcity. Consequently, elevated sTfR levels are expected in iron-deficiency anemia, aiding in its differentiation from anemia of chronic disease. Nonetheless, sTfR levels may also escalate due to increased or ineffective erythropoiesis, complicating analysis. The transferrin receptor ferritin index—defined as the ratio of sTfR to logarithmic serum ferritin—has thus been proposed as a more reliable parameter. Index values >2 suggest iron deficiency, whereas those <1.0 align with chronic disease anemia [58] . End-stage renal disease presents another complicated scenario in clinical iron level assessment. Despite ferritin serving as a marker for iron-deficiency anemia, its reliability diminishes in end-stage renal disease cases [58] . Notably, even at ferritin levels >200 µg/L, administering iron typically elicits a favorable response in terms of anemia. In this case, the theoretical red system iron requirement is not adequately met. In scenarios where high quantities of iron are stored, bioavailable iron shortage is defined as “functional iron deficiency.” Transferrin saturation (TSAT; calculated as serum iron concentration divided by total iron binding capacity) is employed to gauge iron therapy effectiveness. It acts as a predictive measure for iron supplementation success [59] . In individuals afflicted with end-stage renal disease, a TSAT below 20% identifies those most likely to benefit from intravenous iron treatment. The Kidney Disease Outcomes Quality Initiative guidelines recommend initiating iron replacement therapy for dialysis patients when TSAT μg/L [60] . These thresholds suggest bone marrow iron depletion. An elevation of serum ferritin to approximately 800 μg/L typically indicates sufficient iron supplementation. Additionally, the reticulocyte hemoglobin level is being investigated in patients with end-stage renal disease. This assay measures hemoglobin content in newly produced reticulocytes, offering an immediate assessment of iron status within 48 h. However, its use in clinical practice remains limited. Serum ferritin is widely regarded as the most accurate and sensitive indicator among the various blood tests for identifying iron deficiency. Both chronic inflammatory anemia and iron-deficiency anemia demonstrate elevated erythrocyte zinc protoporphyrin concentrations. This occurs as zinc protoporphyrin accumulates in the absence of erythrocyte iron protoporphyrin when iron is unavailable. In comparative analysis, the diagnostic precision of ferritin, in terms of both sensitivity and specificity, exceeded those of transferrin saturation, mean cell volume, and erythrocyte zinc protoporphyrin levels at every threshold [61] . 4.1.2 Ferritin and iron overload Ferritin is employed clinically to both detect and manage iron overload. Iron regulation occurs chiefly at the absorption stage, and the body lacks a physiological mechanism to expel surplus iron. Consequently, iron overload typically stems from abnormal absorption or excessive intake, frequently attributed to recurrent red blood cell transfusions. This iron accumulation primarily affects the liver and heart, causing ongoing damage through free radical activity. Prolonged damage can progressively result in cardiac and hepatic failure, significantly elevating morbidity rates and premature mortality. Clinical manifestations linked to iron deposition encompass arthropathy—notably in the second and third metacarpophalangeal joints, dermatological changes, and endocrine disorders caused by iron accumulation. The advanced stage of iron excess, ”bronze diabetes mellitus,” is marked by a triad of symptoms: skin pigmentation, diabetes due to pancreatic dysfunction, and liver cirrhosis. A prime illustration of iron accumulation is hereditary haemochromatosis, a disorder inherited in an autosomal recessive manner that impacts the body’s iron uptake. The predominant genetic defect leading to the haemochromatosis phenotype originates from the homozygous C282Y allele. This mutation accounts for 90% of primary haemochromatosis cases and represents the most common single-allele genetic disorder among Caucasian populations. The homozygous presence of the C282Y gene modifies the HFE protein, a critical component of major histocompatibility complex class I, which pairs with β2 microglobulin to form a heterodimer. Such mutations alter the structure and disrupt the functionality of cell surface HFE proteins, including those in duodenal crypt cells and macrophages, culminating in enhanced iron absorption. Another mutation, H63D in the HFE gene, can also cause haemochromatosis when paired with a second defective allele, typically C282Y. Iron accumulation phenotypes have also been linked to heterozygosity for these two mutations, particularly in individuals with additional liver damage markers, such as hepatitis or chronic alcohol consumption. Prior to recent findings, C282Y mutation purity was assumed to invariably result in clinical symptoms of iron overload. Nonetheless, a comprehensive longitudinal study involving more than 31,000 individuals in Melbourne, Australia, evaluated the incidence of diseases linked to iron overload in individuals solely carrying the C282Y mutation versus matched controls. Symptoms such as fatigue and high arthritis medication usage were revealed, as well as a greater propensity for liver disease history among men with the C282Y mutation who had serum ferritin levels male and female carriers of the C282Y mutation, 28.4% and 1.2% prevalence of conditions associated with iron overload were reported, respectively. These conditions encompass cirrhosis, hepatic fibrosis, hepatocellular carcinoma, increased levels of aminotransferase, clinically evident symptomatic haemochromatosis, and joint disorders affecting the second and third metacarpals. Additionally, only a single non-C282Y homozygote—recognized as a compound heterozygote—exhibited these iron overload-related pathologies [62,63] . The reduced incidence of such diseases in females is generally attributed to iron loss during menstruation; nevertheless, the potential influence of sex-linked genetic modifiers cannot be disregarded. Given the widespread and unpredictable expansion of hereditary haemochromatosis along with its significant morbidity risk, it is advisable to routinely screen first-degree relatives of individuals diagnosed with this genetic disorder. Screening recommendations for asymptomatic Caucasian males vary. The primary aim of such screening is to detect affected persons before substantial iron has accumulated in their bodily organs, enabling early identification through relatively non-invasive techniques, specifically blood tests, which are generally well-received by both patients and healthcare providers, and allowing for timely and effective intervention. Early therapeutic phlebotomy to normalize iron levels can ensure survival rates on par with those of age-matched individuals not affected by haemochromatosis. Optimal and economical screening methods often involve employing routine iron indices, notably serum ferritin and transferrin saturation levels. Present guidelines advise that high ferritin levels, coupled with TSAT verification [64] . Conversely, a recent extensive screening investigation for haemochromatosis involving approximately 30,000 Caucasian participants indicated that a solitary ferritin marker proves effective. Specifically, serum ferritin levels >1,000 μg/L were exclusively observed in individuals susceptible to severe outcomes, such as cirrhosis [65] . Following the diagnosis of hereditary haemochromatosis, some patients require liver biopsy to assess the extent of end-organ damage. Liver biopsy is advised for patients who show signs of significant, long-term iron accumulation (diagnosed at age >40 years) or severe iron overload (ferritin levels >1000 µg/L), as it provides concrete evidence regarding the degree of iron accumulation and liver injury. Serum ferritin levels are vital in effectively managing haemochromatosis. Inherited haemochromatosis, along with other conditions involving excess iron, is addressed through therapeutic phlebotomy, typically conducted weekly or bi-weekly. Patients are drawn to hypoferritinemia and hemoglobin is carefully monitored to avoid inducing iron-deficiency anemia. Subsequently, hypoferritinemia is sustained through routine phlebotomies aimed at achieving ferritin for men and one to two for postmenopausal women. Regrettably, in the USA, the blood collected during these phlebotomies is not eligible for donation. The accompanying chart illustrates the reduction in ferritin levels over time following therapeutic phlebotomy treatment in individuals diagnosed with hereditary hemochromatosis. Iron accumulation in Africa was initially believed to result exclusively from excessive dietary iron in homebrew, linked to elevated transferrin saturation levels. In the primary case studied, enhanced iron concentrations were observed in both hepatocytes and mononuclear phagocyte system cells, resulting in liver enlargement [66] . Subsequent investigations, however, revealed genetic mutations unrelated to any HLA-associated genes. It was later determined that common variants in the ferroportin 1 gene correlate with elevated serum ferritin levels and reduced hemoglobin levels [67] . Additional genetic anomalies contributing to iron overload and hemochromatosis involve mutations in the transferrin receptor 2, ferroportin, and hemoglobin genes [68] . 4.2 Ferritin in clinical diseases Ferritin serves as an essential resource for medical professionals, facilitating evaluation of prevalent health issues (iron-deficiency anemia) and inherited and acquired conditions (hereditary hemochromatosis and chronic transfusion therapy) associated with excess iron. Typically included in standard blood examinations, serum ferritin is considered the most effective indicator for diagnosing and managing these disorders across various populations, despite certain irregularities, elaborated below. Elevated serum ferritin concentrations may serve as a diagnostic indicator for certain rare and severe autoimmune or inflammatory conditions, including hemophagocytic syndromes and Still’s disease. 4.2.1 Ferritin and iron-deficiency anemia Iron is an essential micronutrient for living organisms, while iron-deficiency anemia is among the most widespread nutrient deficiencies globally, profoundly impacting human nutrition and health across both developed and developing nations. Serum ferritin functions as an indirect indicator of systemic iron reserves and is commonly employed in evaluating anemia. Reduced serum ferritin levels are considered highly specific markers of iron-deficiency anemia and provide a considerably less invasive alternative to the gold-standard—bone marrow biopsy to evaluate stainable iron. Although reference ranges for serum ferritin vary between laboratories, the typical values are generally between 30–300 ng/mL in males and 10–200 ng/mL in females [69] . Iron store depletion is typically inferred when serum ferritin levels <12 ng/mL. Only hypothyroidism and ascorbic acid deficiency, which are rarely mistaken for iron-deficiency anemia, can also reduce these levels [55] . A comprehensive review of diagnostic indicators for iron-deficiency anemia has demonstrated that serum ferritin is the most effective diagnostic tool compared to other tests, including erythrocyte protoporphyrin, transferrin saturation, mean cell volume, or erythrocyte distribution width [61] . This is supported by an area under the receiver operating characteristic curve of 0.95 [61] . In patients with inflammatory, hepatic, or neoplastic conditions, the efficacy of the test varies; however, when interpreted correctly, it remains beneficial. Researchers posited that the sole diagnostic measure for suspected iron-deficiency anemia should be the serum ferritin concentration. They argued that the conventional threshold delineating normal from abnormal levels—typically 12–20 ng/mL—is insufficient for detecting iron-deficiency anemia, even within the general population and notably in individuals afflicted with inflammatory or hepatic disorders. By applying pretest probabilities and likelihood ratios, they recommended adopting a threshold ~40 ng/mL to exclude iron deficiency in most cases. For patients suffering from inflammation or liver disease, a higher benchmark of >70 ng/mL is advocated to exclude iron deficiency more effectively. In a distinct investigation, it was found that while using stainable bone marrow iron—a definitive criterion for detecting iron deficiency—25% of the female subjects displayed serum ferritin concentrations >15 ng/mL, a level once regarded as the lower boundary of the normal ferritin range [56] . This finding confirms the possibility of iron deficiency even when ferritin values fall within accepted norms. The variation in normal ferritin levels between genders has been attributed to widespread iron deficiency among women, often caused by inadequate diets and menstrual bleeding. Consequently, reference ferritin values ought to be established using data from iron-replete populations [70] . Discussions regarding adjustments to the established normal range are ongoing [71,72] . Ferritin, predominantly located within cellular structures, also circulates in serum, serving as an iron transporter [73] . Although serum ferritin contains less iron than its cellular counterpart [74,75] , it contributes significantly to iron delivery to cells [76] . Commonly, serum ferritin measurements are utilized to gauge bodily iron content and serve as a crucial diagnostic marker in blood analyses. Elevated levels of serum ferritin may indicate conditions of iron excess, such as hereditary haemochromatosis, or transfusion treatment outcomes, whereas diminished levels often suggest iron-deficiency anemia [61] . Research indicates a direct association between increased serum ferritin levels and disease progression. Moreover, diagnostic evidence confirms the superior efficacy of serum ferritin in diagnosing iron deficiency compared to iron saturation measurements in erythrocytes or transferrin [61] . Given the alternative cellular mechanisms for iron absorption, such as CD44 and lipocalin-2.51 [77,78] , transferrin iron saturation may not serve as an entirely dependable indicator of total body iron stores. Furthermore, determining serum ferritin concentrations fails to reveal whether the ferritin exists as a monomer or polymer, nor does it indicate whether the ferritin structure is vacant, filled with iron, or in between. Considering these variables, the iron content assessed via serum ferritin can exhibit substantial variability among individuals [56] . A direct assessment of serum iron might better reflect actual body iron levels. While ferritin measurements can provide insights regarding iron storage, iron transportation, and inflammatory status, they should not be exclusively relied upon as definitive markers of iron status for diagnostic or prognostic applications. 4.2.2 Ferritin and chronic kidney disease In patients with chronic kidney disease, serum ferritin measurements do not provide reliable indications of bioavailable iron levels. Furthermore, methemoglobinemia does not accurately reflect iron reserves in these patients [79] . Importantly, while approximately 50% of maintenance hemodialysis patients demonstrate serum ferritin concentrations exceeding 500 ng/mL, these elevated levels do not correlate with the iron available for erythropoiesis. In roughly one-third of these patients, elevated ferritin levels may be attributed to inflammation [80,81] . In addition, hemodialysis patients with serum ferritin >800 ng/mL have higher C-reactive protein (CRP) levels and poorer malnutrition inflammation scores [82] . The Kidney Disease Outcomes Quality Initiative guidelines for such patients suggest a serum ferritin level of 800 ng/mL as the upper limit for intravenous iron therapy. Absolute iron deficiency is defined using another laboratory measure (transferrin saturation <20%) or serum ferritin <100 ng/mL, which are both associated with deficiency or near-deficiency of bone marrow stainable iron [60] . 4.2.3 Ferritin and malignant tumors Ferritin has been identified as a possible prognostic marker in various cancers, including breast cancer [83,84] , ovarian cancer [85] , pancreatic cancer [86] , and advanced non-small cell lung cancer [87] . Ferritin is expressed to varying degrees in a wide range of tumors, containing hepatocellular carcinoma, hematological malignancies, breast cancer, and pancreatic cancer. Serum ferritin is commonly employed as a second marker for the detection of primary liver cancer. Recent studies have shown that the tumor cells of patients with various solid tumors can synthesize and produce large amounts of ferritin, and elevated ferritin levels play a critical role in the differentiation of benign and malignant tumors, diagnosis, the extent of lesions, metastasis of tumor cells, and treatment efficacy. For example, in early-stage hepatocellular carcinoma patients when the serum alpha-fetoprotein test value is normal, the detection of elevated serum ferritin can help diagnose hepatocellular carcinoma, improving the early diagnosis rate, after excluding the influence of other diseases. A substantial body of research indicates that in various cancers, iron and ferritin levels deviate from normal [88] . Frequently, cancer cells demonstrate heightened iron concentrations, possibly resulting from enhanced uptake and retention of cellular iron, or a reduction in its export. This often correlates with elevated ferritin levels in cancerous cells relative to healthy tissues. Accumulating levels of intracellular iron play several roles in cancer pathogenesis, encompassing metabolism, tumor proliferation, and metastases development. Ferritin expression is elevated across numerous cancer types, enhancing iron accumulation while mitigating iron-dependent ROS production [89,90] . Elevated serum ferritin levels are related to unfavorable outcomes in various cancers, including breast cancer [91,92] , colorectal cancer [93] , hepatocellular carcinoma [94] , lung cancer [95,96] , diffuse large B-cell lymphoma [97] , prostate cancer [98] , and oral cancer [99] . Notably, serum iron concentrations are more indicative and diagnostic of cancer than ferritin levels, implying a lack of correlation between these two markers [100] . This discrepancy could stem from patient variations in serum ferritin iron content. Often, cancer is accompanied by anemia, and heightened ferritin levels might indicate either iron buildup within tumor cells or inflammation associated with cancer in tumor-related macrophages. In certain instances, a rise in circulating ferritin levels may also correlate with changes in its composition towards species richer in hydrogen [101] . For instance, in cases of malignant histiocytosis, serum ferritin primarily comprises the ferritin H type [102] . The reasons for these modifications remain unclear. Nonetheless, in neuroblastoma, elevated serum ferritin levels have been linked directly to ferritin secretion by the tumor. In experiments involving nude mice implanted with human neuroblastoma cells, human ferritin was identified in the serum [103] . Nonetheless, studies have revealed no variation in the ratio of acidic (H-rich) to basic (L-rich) isoferritins in the serum of neuroblastoma patients, indicating that the quantity or type of ferritin secreted by a tumor has no noticeable impact on the composition of serum ferritin [104] . Fig. 3 Ferritin in malignant tumor diagnosis and treatment. Breast Cancer . Throughout the last two decades, the incidence of breast cancer has grown rapidly worldwide, with the absolute number of cases elevated 1.4-fold globally and breast cancer prevalence rising by 30% to 40% in most countries and regions. In 2020, global-scale data from the World Health Organization showed 2.26 million new breast cancer diagnoses per year, officially replacing lung cancer as the top malignant tumor in women. Excess iron may enhance carcinogenesis. Studies using animal models corroborate the hypothesis that an abundance of free iron may induce carcinogenesis. Recent investigations, including a review by Kabat and Rohan [105] , have examined the potential carcinogenic effects of excessive free iron, particularly its role in breast cancer. They observe that postmenopausal women face an elevated risk of cancer, aligning with the theory that heightened iron reserves could foster the onset of cancer. They suggest oxidative stress arises from ROS, and ROS production is facilitated by unbound iron. Iron in the form of ferric iron (Fe 3+ ) is liberated from ferritin and iron-laden hemoflavin and is transformed into ferrous iron (Fe 2+ ). This reduction process catalyzes the generation of hydroxyl radicals (*OH) when exposed to superoxide and hydrogen peroxide (H 2 O 2 ). Hydroxyl radicals, potent oxidizing agents, facilitate processes such as lipid peroxidation, mutagenesis, the fragmentation of DNA strands, and both the activation and suppression of oncogenes. However, the effects of products resulting from lipid peroxidation on cancer development are still subject to debate, presenting inconsistent findings. Moreover, iron accumulation is observed as individuals age, particularly in postmenopausal women, potentially elevating their risk of developing age-related cancers. Yet, whether there is an age-related increase in iron levels within breast tissue remains uncertain [106] . Ferritin concentrations in cancerous tissues are six-fold greater than those in either normal or benign tissues [84,107,108] . Furthermore, both transferrin and transferrin receptor protein levels are elevated in breast cancer tissues [109–111] . In a comparison of preoperative cancer patients, 41% of women exhibited elevated serum ferritin levels, in contrast to women without breast cancer who generally maintained normal ferritin levels. Furthermore, iron concentrations in breast cancer biopsy specimens were quintupled relative to those in benign breast tissue [112] . To this point, research has not conclusively demonstrated ferritin to be a direct contributor to cancer development; its elevation may simply reflect cancer presence. It is hypothesized that iron could interact with recognized factors of breast carcinogenesis, including estradiol, ethanol, and ionizing radiation, potentially worsening the condition. Iron accumulation may enhance ROS production, leading to lipid peroxidation and DNA damage. Should subsequent investigations verify that heightened levels of iron in the body aid cancer progression, the use of chelating agents to reduce this risk may emerge as an effective approach [113] . In patients presenting with newly diagnosed, locally recurrent, or metastatic breast cancer, preoperative serum ferritin concentrations are increased [110] . A ten-fold elevation in tissue ferritin was observed in cytoplasmic extracts from breast cancer cells compared to those from benign breast tissue. Furthermore, electron microscopy revealed a high abundance of ferritin within malignant epithelium, in contrast to its scarcity in benign epithelium and connective tissue [108,114] . Another investigation revealed a predominance of ferritin in the stroma and histiocytes that encircle tumor cells, indicating that the observed elevation in serum ferritin concentrations among breast cancer patients may be attributed to stromal reactions rather than direct synthesis by the tumor [111] . Although no conclusive evidence has been established to support the hypothesis that ferritin directly causes tumorigenesis, excessive iron and disturbances in iron regulation may contribute to breast cancer development. As ferritin increases, breast cancer progresses; thus, ferritin is significant in monitoring the course of breast cancer. Ovarian cancer is considered the deadliest malignancy among gynecological tumors and constitutes the primary cause of mortality within gynecological diseases. Furthermore, it ranks as the fifth most prevalent cause of mortality among the general female population [115] . Owing to the absence of characteristic clinical indicators during ovarian cancer’s initial phases, approximately 75% of cases are identified in advanced stages. Additionally, over 70% of patients experience a recurrence post-treatment, significantly and adversely affecting prognosis. This is further compounded by the low predictive value of available screening tests. Comprehensive gynecological assessments, complemented by transvaginal ultrasonography and laboratory biomarker analysis including cancer antigen-125 (CA-125) quantification, are considered essential components of early detection protocols. However, these approaches have not been demonstrated to improve either the morbidity or mortality rates associated with this malignancy [116] . In clinical practice, CA125 testing, HE4 testing, and combined CA125 and HE4 testing are commonly used as adjunctive diagnostic methods. Typically, CA-125 levels are assessed alongside imaging techniques. This biomarker tends to be heightened in the majority of epithelial ovarian cancer cases, although it is only present in about 50% of early-stage cases [117] . Notably, postmenopausal women exhibit greater specificity and positive predictive values compared to their premenopausal counterparts. Elevated CA-125 levels may also manifest in various non-malignant conditions, including endometriosis, gestational states, ovarian cysts, and peritoneal inflammatory disorders. Consequently, research to identify additional biomarkers to enhance the diagnostic accuracy for ovarian cancer is ongoing. One promising candidate is Human Epitope Protein 4 (HE4), which has demonstrated increased sensitivity, particularly in plasmacytoid and endometrioid ovarian cancer subtypes, detecting nearly all cases in these categories. Recent research suggests that elevated levels of both CA-125 and HE4 could indicate ovarian malignancy, potentially serving as valuable indicators in future diagnostic protocols [118] . Moreover, CA-125 is instrumental in computing the Risk of Malignancy Index (RMI), which incorporates data from transvaginal ultrasound and menopausal status. An RMI >200 correlates with a markedly elevated probability of malignant disease, achieving a specificity To further improve the early diagnosis rate of ovarian cancer and the survival rate of female patients, many scholars have proposed that since ferritin and CA125 have low sensitivity in diagnosing early lesions of ovarian cancer, they can be combined with other marker tests to improve the positive rate of diagnosis. To evaluate the diagnostic efficacy of diverse tumor markers in epithelial ovarian cancer, clinical data were collected from patients diagnosed with epithelial and benign ovarian tumors. We utilized a combined assay of tumor markers (CA125, CA242, AFP, β-HCG, CEA, CA199, NSE, Ferritin, CA153, and HGH) for this comparison. Research conducted by Shan Dongyong et al. found that CA125 outperformed the other nine markers in terms of sensitivity, Jordon’s index, and overall diagnostic effectiveness when used alone. However, when combined, the sensitivity of CA153, CA199, CA242, Ferritin, and CEA surpassed that of CA125. The biomarkers CA153, CA199, CA242, Ferritin, CEA, and CA125 demonstrate enhanced sensitivity compared to CA125 alone. Specifically, the sensitivities of the CA125+CEA and CA125+Ferritin+CEA combinations were 89.2% and 90.8%, respectively. These combinations also exhibit superior diagnostic efficiency (84.1%), surpassing the performance of alternative marker combinations. Notably, the Yoden index for CA125+CEA stands at 0.616, exceeding the indices of alternative combinations. Consequently, it is evident that CA125 possesses substantial diagnostic value for epithelial ovarian cancer. Moreover, the synergistic evaluation of these serum tumor markers yields greater sensitivity and specificity in detecting this type of cancer [120] . The simultaneous measurement of CA125 and ferritin is considered a valuable approach for the diagnoses of ovarian cancer and benign ovarian tumors, and differential diagnosis between them. This methodology may contribute significantly to the development of novel strategies for the early detection of ovarian cancer in future clinical practice. Primary Liver Cancer . The liver serves a pivotal function in the human body. It mainly comprises the hepatic lobules and surrounding connective tissue, with hepatocytes forming the fundamental structural and functional units. There are many factors that can negatively affect liver cells and lead to their damage. Severe damage to hepatocytes leads to liver dysfunction, which may result in secondary dysfunction of the entire organism. This deterioration can progress to fibrosis, hepatic failure, and ultimately result in primary liver cancer. Hepatocellular carcinoma has been identified as the sixth most prevalent malignancy globally and ranks as the fourth leading cause of cancer-related mortality worldwide. In a retrospective analysis conducted by Meier et al. [121] , the correlation between ferritin concentration and mortality in individuals suffering from end-stage liver disease was investigated. The study revealed a marked association: elevated ferritin levels were significantly correlated with mortality within 90 days. Notably, over half of the patients exhibiting ferritin levels >1030.5 µg/L succumbed within 11 days. Furthermore, the mortality rate reached 83% among these patients by the 90-day mark. These findings suggest that serum ferritin measurements may be employed as a prognostic indicator for evaluating clinical outcomes in patients with advanced hepatic disease. Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocellular carcinoma. HCC ranks as the third leading cause of cancer-associated mortality globally and constitutes the primary cause of mortality among patients suffering from cirrhosis [122] . HCC is typically identified at advanced stages, rendering therapeutic intervention particularly challenging. Chronic hepatitis B virus (HBV) infection has been established as the most prevalent risk factor for HCC [122] . Research suggests that the assessment of ferritin concentrations may prove valuable in the early detection of HCC [123] . In vitro experimental studies have shown that iron exposure induces enhanced ferritin synthesis in hepatocellular carcinoma cell lines and promotes tumor cell growth [124,125] . Studies have demonstrated that ferritin levels are significantly elevated in patients with HCC compared to both healthy individuals and patients suffering from alternative hepatic diseases [126–128] . At this stage, we believe that ferritin has a guiding, but not unique, role in confirming the diagnosis of primary liver cancer. Fig.4 Ferritin tumor therapy applications.(a) Biomineralization-inspired synthesis of copper-ferritin sulfide nanocages as cancer therapeutic applications. Reprinted from Ref. [129] with permission granted by American Chemical Society. (b) Panitumumab-conjugated platinum-core pH-sensitive Apoferritin nanocages for targeted colorectal cancer therapy. Reprinted from Ref. [130] with permission obtained from American Chemical Society. (c) Enhanced tumor immunotherapy through multivalent anti-PD-L1 nanobodies assembled utilizing ferritin nanocages. Described in Ref. [131] with permission provided from Wiley. (d) Apoferritin Nanocage delivers a combination of microtubule- and nucleus-targeted anticancer drugs. Reprinted from Ref. [132] with permission from American Chemical Society. 4.2.4 Relationship between ferritin and chronic liver disease Chronic Liver Disease . The liver is recognized as the principal repository for iron in the human body. It is also where ferritin is synthesized and stored in the largest amount, and the inflammatory response of hepatocytes increases ferritin synthesis significantly. Ferrar et al. [133] found that ferritin could be utilized as an indicator of therapeutic efficacy for interferon and ribavirin in hepatitis C treatment. Their investigation encompassed 206 patients diagnosed with chronic hepatitis C, wherein a significant correlation was observed between ferritin concentration and hepatic fibrosis prior to therapeutic intervention. After treatment, elevated ferritin levels were identified as an independent factor reflecting antiviral efficiency response, with higher antiviral efficacy when ferritin was elevated 2.5-fold. However, another study showed an independent correlation between high ferritin and a diminished response to interferon therapy for hepatitis C. Therefore, additional research is warranted to elucidate whether ferritin can be reliably employed as a predictive factor for the treatment of hepatitis C. Non-alcoholic fatty liver disease (NAFLD) is currently recognized as the most prevalent chronic hepatic disorder globally. NAFLD manifests itself in a wide range of liver injuries including non-alcoholic steatohepatitis, hepatic fibrosis, and cirrhosis, which can be complicated by hepatocellular carcinoma and liver failure. NAFLD exhibits a strong association with metabolic syndrome and has emerged as a predominant cause of chronic liver disease worldwide, with a rapidly escalating prevalence among the general population (approximately 20%–30%), corresponding to the global epidemics of obesity and type 2 diabetes mellitus [134,135] . The clinical and pathological spectrum of NAFLD encompasses various liver disorders, from simple steatosis to non-alcoholic steatohepatitis (NASH). NASH represents a more aggressive manifestation of NAFLD that may progress to cirrhosis and associated complications [136,137] . Given the potential progression from NAFLD to NASH, hepatic fibrosis, cirrhosis, and related complications, the identification of predictive factors for NAFLD and its advanced forms is of considerable clinical importance. Although liver biopsy continues to be regarded as the ”gold standard” for assessing hepatic injury in NAFLD, numerous non-invasive diagnostic tools have been developed as alternatives to histological examination, with FiberScan demonstrating particular promise. Among various serum biomarkers, uric acid and ferritin have been identified as potential predictors of NAFLD severity. Kowdely et al. [138] has established that elevated serum ferritin concentrations serve as an independent predictor of both the severity of hepatic fibrosis and the extent of pathological damage in NAFLD. Their investigation demonstrated that SF exceeding 300 ng/mL in female patients and 450 ng/mL in male patients correlated significantly with increased alanine aminotransferase and aspartate aminotransferase (AST), and that pathological damage such as steatosis, fibrosis, and hepatocyte ballooning was more severe in these patients. Complementary research has also indicated that serum ferritin measurements may possess predictive value for NAFLD development in pediatric populations with obesity [139] . About one-third of patients with NAFLD present with elevated serum ferritin and hepatic iron overload, a condition that has been designated as ”metabolic iron overload syndrome.” The heightened serum ferritin concentrations observed in NAFLD patients appear to demonstrate associations with both insulin resistance and hepatocellular injury. We found that serum ferritin, as a biological indicator, may maintain a close relationship with NAFLD severity and be useful for monitoring the occurrence and development of NAFLD. Thus, it may be evaluated as a non-invasive diagnostic approach for hepatic steatosis. Cirrhosis . High serum ferritin is considered a significant prognostic indicator of poor outcomes in advanced chronic liver disease and, unlike its cytoprotective and antioxidant activities, may play a deleterious pathophysiological role in various pathogenic conditions. More than a decade ago, Walker et al. [140] found high serum ferritin to be a risk factor for predicting death at 180 days and 1 year in cirrhotic patients awaiting transplantation, independently of MELD score or HCC. These findings were supported by a subsequent study involving 318 patients with decompensated cirrhosis, which confirmed that increased serum ferritin levels were strongly associated with disease severity and served as an independent predictor of short-term liver-related mortality. Nevertheless, another large cohort study based on 1079 patients showed that serum ferritin has limited value as a prognostic indicator of survival before and after liver transplantation [141] . Notably, Fallet et al. reported a U-shaped association between ferritin levels and survival, with both hypo- and hyperferritinemia linked to reduced patient outcomes. As previously discussed, the prognostic significance of serum ferritin appears to be influenced by disease severity. Comparative analyses revealed significant disparities in clinical and biochemical profiles between patients with high versus low ferritin levels, suggesting that confounding factors may modulate its predictive accuracy. A recent investigation of 257 patients with decompensated cirrhosis, the first large-scale analysis to examine the association between serum ferritin and mortality using propensity score matching analysis, suggested that baseline variables were balanced between groups with different serum ferritin levels after propensity score matching. Serum ferritin also lost its predictive value when various clinical and biochemical parameters of the body were adequately corrected. Consequently, the end-stage liver disease score remained the sole independent predictor of death at 180 days. These findings challenge the utility of serum ferritin as an independent prognostic marker in decompensated cirrhosis [142] , suggesting it should not be relied upon for mortality risk stratification in this patient population. Chronic Alcoholic Liver Disease (ALD), as the standard of living improves, the consumption of alcohol or alcoholic beverages has increased dramatically in China, and the incidence and prevalence of ALD has gradually risen. Globally, the rate of alcohol abuse among adolescents is also increasing year by year, and chronic ALD has become a global public health problem. Chronic ALD is a disease of liver cellular structure or liver dysfunction caused by prolonged and heavy alcohol consumption. The disease usually starts with fatty deposits in the liver cells and progresses to alcoholic hepatitis, alcoholic liver fibrosis, and alcoholic cirrhosis, and if alcohol abuse continues, it can lead to extensive hepatocellular necrosis, leading to liver failure and liver cancer. Increased serum glutamyltransferase is a good indicator for recognizing alcohol-induced liver damage, but its levels are affected by many drugs. Alcoholism with viral hepatitis is also relatively common, and the pathogenesis of ALD is complex, with direct and indirect damage to the liver caused by alcohol, as well as a strong association with nutritional status and genetic susceptibility. Animal studies have demonstrated that chronic alcohol consumption promotes excessive hepatic iron accumulation. Iron exacerbates oxidative stress by catalyzing the conversion of superoxide and hydrogen peroxide into highly reactive oxidants, including hydroxyl or pertechnetate radicals, or the Fenton reaction of hypertechnetate radicals. Micronutrient Sprinkles can interfere with normal iron metabolism, resulting in aberrant hepatic iron deposition, which contributes to liver injury. This dysregulation manifests as reduced serum iron levels and a compensatory increase in ferritin. Li Zhiguo and other scholars tested serum iron and serum ferritin in patients with varying stages of ALD. The results showed that, with aggravation of the degree of ALD, patient serum iron content gradually decreased and serum ferritin and AST gradually increased. This indicates that serum ferritin, combined with AST, is important in diagnosing patients with ALD. Consequently, serum ferritin may serve as a useful indicator to observe the efficacy of clinical treatment for chronic alcoholism. 4.2.5 Ferritin and coronary artery disease Iron deficiency is prevalent in approximately 60% of patients with coronary artery disease, the leading cause of mortality in developed nations. Recent reviews have addressed the association between excess iron and heightened cardiovascular risk [143] . Epidemiological research suggests that elevated serum ferritin levels are linked to increased incidence of coronary artery disease and myocardial infarction, as observed in a study with an average follow-up duration of three years [144] . The likelihood of myocardial infarction was elevated by a factor of 2.2 in males with serum ferritin levels ≥ 200 μg/L. This association was more pronounced in individuals with elevated LDL concentrations. In a separate investigation, Klipstein Grobusch et al. [145] identified smoking status (current or former) as a modifier amplifying the association between high serum ferritin and myocardial infarction risk. In contrast, iron reduction has been linked to a decreased incidence of myocardial infarction and other cardiac events. Among 31 patients who attained iron depletion through blood sampling, there were notable reductions in HDL, LDL, triglycerides, fibrinogen, and blood pressure. In a related investigation, a prospective follow-up over 5 years involving over 2,500 Finnish males demonstrated that blood donors experienced an 86% decrease in myocardial infarction incidents compared to non-donors [146] . Nevertheless, many epidemiological studies have failed to establish a definitive causal relationship between iron status and cardiovascular disease risk. The role of elevated ferritin levels—whether they contribute pathogenically to coronary artery disease progression or merely reflect an epiphenomenon of the underlying disease process—remains unresolved. To address this question, an animal model of atherosclerosis should be employed, enabling transgenic overexpression of ferritin L or ferritin H to directly investigate their mechanistic involvement. 4.2. 6. Acute inflammatory response The acute phase response encompasses a cascade of cellular reactions triggered by host cells in response to injury, trauma, infection, autoimmune disorders, or tumors [147] . The acute phase response is designed to inhibit the process of cellular injury while promoting the process of tissue repair [148] . Acute phase proteins, synthesized predominantly by hepatocytes, are a subset of reactants generated during the acute phase of inflammation. Research indicates that cytokines significantly influence the synthesis of these proteins. Notably, pro-inflammatory cytokines, including interleukin-1β (Il-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (Il-6) promote the synthesis of these proteins [149] . Conversely, interleukin-10 (Il-10) and transforming growth factor beta (TGF-β), recognized as anti-inflammatory cytokines, inhibit their production [150] . Liver-derived acute phase reactants can be categorized based on their expression patterns during inflammation. Proteins exhibiting significant overexpression are classified as ”positive” acute phase proteins (APP), such as Hp, SA, fibrinogen, Cp, AGP, alpha-1-antitrypsin, lactoferrin, and CRP. Conversely, proteins demonstrating reduced synthesis are designated as ”negative” APPs, including albumin, transferrin, and transthyretin [151] . As a notable acute phase reactant, ferritin is characterized by elevated levels in both intracellular and extracellular environments. It exists in diverse forms, influenced by the proportions of its two subunits [152] , H and L, which each play distinct roles in determining the metabolic characteristics of ferritin [153] . Ferritin composed predominantly of H subunits plays a pivotal role in intracellular iron transport kinetics, facilitating the swift accumulation and release of iron [154] . In contrast, ferritins rich in L subunits, which are more stable and capable of holding greater amounts of iron, tend to increase preferentially during periods of iron surplus [155,156] . Upregulation of both the H and L ferritin subunits is beneficial in combating oxidative stress [157] . Nonetheless, inflammatory conditions predominantly stimulate the synthesis of ferritin with a higher content of H subunits, highlighting its crucial role in rapid iron sequestration and the reduction of available iron within cells. Moreover, during inflammation, the increased presence of H-subunit-rich ferritin offers enhanced protection against the oxidative damage caused by hydroxyl radicals, as these ferritins contribute minimally to iron release during the Fenton reaction [158] . Ferritin functions as an acute phase reactant that binds and sequesters iron within cells. This protein has a crucial effect on iron homeostasis, especially during inflammatory processes, to shield the body from infections, injuries, and malignancies. Notably, the Fenton reaction occurs when ferrous iron (Fe+2) interacts with H 2 O 2 , generating hydroxyl radicals, which are among the most potent ROS [159] . These radicals support the function of neutrophils and macrophages in phagocytosis by engaging with the cellular constituents of the engulfed material. In a setting of inflammation and infection, elevated production of these radicals is observed. These ROS subsequently permeate the fluids and tissues adjacent to inflamed areas, causing extensive cellular damage by interacting with cellular components [160] . Thus, by enhancing ferritin concentrations, which reduces available iron, it is possible to mitigate the detrimental impacts of free radicals at inflammation sites. 4.2.7 Relationship between ferritin and autoimmune disease Increased ferritin concentrations are observed across a range of autoimmune disorders. It is believed that this rise in ferritin is due to cytokines promoting the synthesis of ferritin as a secondary response to immunostimulation in these diseases [161,162] . Rheumatoid arthritis , a chronic autoimmune disorder, is marked by joint inflammation and heightened levels of TNFα and IL-1α [163] . While peripheral serum ferritin levels in rheumatoid arthritis patients may remain within normal limits, studies indicate increased ferritin levels in both synovial fluid and synovial cells [164] . Contrastingly, patients diagnosed with systemic juvenile arthritis exhibit elevated serum ferritin at onset [165] . As treatment progresses, ferritin levels diminish and serve as indicators for physicians when prescribing glucocorticoids, as noted in the same study. C-reactive protein shows a strong association with the activity of rheumatoid arthritis, and although it is also correlated with serum ferritin levels, this correlation is less pronounced [166] . Systemic Lupus Erythematosus (SLE) is recognized as a chronic autoimmune condition, impacting numerous organs and tissues through a range of autoantibodies and widespread inflammation [167] . Typically, SLE patients do not demonstrate elevated acute-phase protein levels unless concurrent infection is present. Nevertheless, increased concentrations of iron-binding proteins have been observed in the urine of lupus sufferers who also have nephritis [168] . Additionally, another investigation has reported higher levels of serum ferritin in individuals exhibiting greater disease activity [169] . Multiple sclerosis represents an additional autoimmune disorder characterized by the demyelination of the central nervous system [170] . Iron, essential for myelin synthesis, plays an essential role; aberrations in iron homeostasis have been associated with the pathogenesis of this disorder [171] . The transportation of iron to cerebral structures is predominantly facilitated by transferrin. Transferrin receptors are concentrated within grey matter regions, whereas ferritin binding sites are principally situated in white matter domains. Furthermore, demyelinated regions in multiple sclerosis patients exhibit significant modifications in transferrin and ferritin concentrations [172] . Whether the observed reduction in ferritin binding directly contributes to demyelination or merely represents a consequence thereof remains to be elucidated. Additionally, a study involving 150 individuals diagnosed with multiple sclerosis revealed that hyperferritinemia was observed more frequently among those suffering from mixed dementia than in healthy control subjects [173] . Other autoimmune diseases linked with elevated ferritin levels, such as polymyositis and dermatomyositis, are particularly prevalent in older individuals compared to their younger counterparts [174] . Furthermore, patients suffering from thyroiditis exhibit increased levels of ferritin, which typically diminish following anti-inflammatory treatment[ 175 ]. 4.2.8 Ferritin and neurological disorders There is growing evidence suggesting iron accumulation serves as a critical factor contributing to neuronal death in neurodegenerative diseases. Ferritin, a hollow iron storage protein comprising 24 subunits of both ferritin heavy chain (FTH) and ferritin light chain (FTL) types, plays a fundamental role in iron homeostasis maintenance. Recent investigations revealing the presence of extracellular ferritin and ferritin within exosomes indicate that this protein may extend beyond its traditional intracellular storage function to participate significantly in the regulation of tissue and systemic iron homeostasis. Parkinson’s disease represents the second most prevalent neurodegenerative condition affecting humans, wherein tremor at rest, muscle rigidity, bradykinesia, and postural instability are the main motor symptoms; some patients may also exhibit by non-motor symptoms including olfactory dysfunction, sleep disturbances, autonomic dysfunction, and cognitive impairment. The characteristic pathological hallmarks of Parkinson’s disease encompass the degeneration of dopaminergic neurons within the midbrain substantia nigra, resulting in diminished dopamine secretion, alongside the formation of intracytoplasmic inclusion bodies termed Lewy bodies within dopaminergic neurons. The pathogenesis is still unclear, but it is increasingly recognized that genetic components, inflammation processes, oxidative stress, and abnormal iron metabolism collectively contribute to both the initiation and progression of Parkinson’s disease. The role of iron in neurological disorders has become a focal point of extensive research, prompted by observations of elevated iron concentrations in the brains of individuals with Parkinson’s disease and other neurodegenerative conditions. Although proteins governing systemic iron homeostasis are similarly expressed in cerebral tissues, functional deficiencies in these proteins through genetic disorders rarely manifest as pathological iron imbalance within the brain. Iron distribution throughout the brain exhibits considerable regional variation. Iron concentrations reach their peak within the basal ganglia and exhibit levels similar to those observed in the liver. Moreover, astrocytes demonstrate a marked abundance of iron, reinforcing the notion that these, along with various other glial cell types, contribute significantly to the storage and management of iron. The blood–brain barrier is believed to segregate cerebral iron balance from systemic iron regulation, effectively mitigating the impact of systemic fluctuations on central nervous system stability [176] . Individuals afflicted with Parkinson’s disease exhibit elevated iron concentrations within their cerebral structures; notably, the substantia nigra compacta experiences the most profound escalation. Disease severity in living patients can be assessed via magnetic resonance imaging (MRI). Comparative autopsy examinations of brain tissue from normal individuals across various age groups reveal a correlation between increased nigrostriatal echogenicity and elevated levels of iron, alongside higher concentrations of L- and H-ferritin. These conditions coincide with decreased neuromelanin levels [177,178] . This suggests that the cellular environment becomes deleterious, fostering the generation of oxygen radicals and consequent cellular harm. In the brain, ferritin is predominantly localized within oligodendrocytes, astrocytes, and microglia, while it is notably absent in neurons. During the progression of Parkinson’s disease, ferritin cores within the substantia nigra display markedly increased density and an elevated iron content compared to those observed in healthy individuals. Microglia rich in ferritin are typically situated adjacent to neurons that either contain melanin or are undergoing degeneration. Primarily, neuronal iron is bound to neuroligin. The role of neurorelaxin, whether as a cytoprotective agent in the sequestration of transition metals or as a facilitator of cytotoxicity when iron is liberated within neurons, remains uncertain. In Parkinson’s disease, the degenerating neurons exhibit both neurorelaxin presence and elevated iron levels, in contrast to surviving neurons, which lack neurorelaxin, contain minimal iron, and exhibit greater resistance to oxidative stress [177,178] . Friedreich’s ataxia , an autosomal recessive disorder, is marked by degeneration affecting sensory neurons, cerebellar cells, and cardiac myocytes. This disorder stems from the expansion of GAA triplet repeats, impairing mitochondrial iron–sulfur cluster synthesis. The impaired formation of these clusters, coupled with unstable iron deposits, precipitates oxidative stress and neurodegeneration. Notably, iron deposition in this disease is highly localized and does not necessarily correlate with systemic indicators of iron excess, such as elevated serum ferritin levels. In Friedreich’s ataxia, iron predominantly accumulates in the dentate nucleus, a detail observable in MRI studies [179] . Recent therapeutic strategies, including the use of the membrane-permeable chelator deferiprone, have demonstrated potential in mitigating this iron buildup. R2* MRI detected a reduction in iron levels within the dentate nucleus using deferiprone in a small group of adolescent Friedreich’s ataxia patients [180] . More remarkably, neurological manifestations associated with Friedreich’s ataxia exhibited preliminary indications of improvement. These findings further establish the critical role of iron homeostasis in both the pathogenesis and therapeutic management of neurological disorders. Neurological ferritinopathy , a hereditary disorder of autosomal dominant inheritance, primarily affects the extrapyramidal system and arises from mutations in the ferritin light chain. Manifestations include chorea, dystonia, spasticity, and dysarthria. It is postulated that these genetic alterations disrupt ferritin’s assembly, diminishing the capacity of brain cells to store iron, thus precipitating iron-induced cellular damage [181] . Notably, all individuals diagnosed with this condition exhibit dystonia due to iron accumulation in the basal ganglia. Despite the ubiquitous presence of the ferritin light chain mutation in all bodily cells of affected patients, abnormalities in systemic iron regulation are generally absent, except for decreased serum ferritin levels. It remains unclear whether this indicates a particular vulnerability of brain cells to iron-related damage or if the ferritin light chains play a distinct role in these specific neurons. The similar pathological features observed in neuroferritinopathy and copper-cyaninemia suggest that shared iron-dependent pathways may underlie the neurodegenerative processes in both conditions. Restless Legs Syndrome , a neurological condition, manifests primarily through discomfort in the legs that predominantly arises at night during rest. It is marked by an irresistible compulsion to move the limbs. Notably, in an Italian study, 26 per cent of pregnant women had symptoms of restless legs syndrome, of which only 10 per cent had symptoms prior to pregnancy. Research conducted by Kotagal and Silber [182] demonstrated that a significant majority (83%) of patients with restless legs syndrome, specifically 24 individuals, exhibited lower levels of serum ferritin, indicating that iron deficiency may be a distinguishing trait of this condition. Contrarily, a comprehensive study in Italy found no significant differences in ferritin levels between those with and without the syndrome. Yet, this study did reveal elevated concentrations of serum soluble transferrin receptors in affected patients, potentially signifying an initial stage of iron deficiency [183] . Research indicates that patients suffering from restless legs syndrome (RLS) exhibit notably reduced levels of ferritin in their spinal fluid when compared to a control group; however, the levels of serum ferritin and transferrin remain comparable between these two groups. This disparity suggests that the origin of the disease may be primarily central [184] . Further studies by Connor have shown a marked reduction in both iron and ferritin heavy chains, alongside an elevated presence of transferrin within the substantia nigra in individuals with RLS [185] . Consequently, RLS might be considered a functional disorder, stemming from compromised iron availability to cells containing neurofibrillary protein. Typically, these patients receive treatment with dopaminergic medications. Assessing and potentially supplementing the iron levels in RLS patients is advisable if serum indicators reveal an iron shortfall. 4.2.9 Methemoglobinemia and methemoglobin syndrome For many years, a well-established link has existed between elevated ferritin levels and a spectrum of inflammatory and infectious conditions. However, exceedingly high ferritin concentrations are recognized as a distinct pathological condition. For instance, when ferritin exceeds 400 ng/mL, the condition is identified as methemoglobinemia [186] . These extreme ferritin levels are linked to a constellation of symptoms known as ”methemoglobinemia syndrome” (Shoenfeld syndrome)[ 187 ]. Moreover, Piperno [188] has explored several disorders characterized by heightened ferritin levels, collectively termed ”hyperferritinemia.” The research highlights that these disorders differ from established iron overload pathologies, which typically arise from congenital or acquired conditions predominantly associated with excess iron. Shoenfeld et al. [187] propose that methemoglobinemia is a continuation of a series of disorders known as ”methemoglobin syndromes”. The diseases discussed herein comprise Adult-onset Still’s Disease (AOSD), catastrophic antiphospholipid syndrome (cAPS), macrophage activation syndrome (MAS), and infectious shock. This article synthesizes the clinical, laboratory, and therapeutic commonalities of these conditions, ultimately advocating for their classification under a unified category termed “methemoglobinemic syndrome.” Notably, before 2013 and before the term “methemoglobinemic syndrome” was coined, research by the same group indicated that defining such a term was initially unfeasible. In 2013, prior to the adoption of the term ”methemoglobinemia syndrome,” research conducted by the same team indicated that methemoglobinemia might serve as an initial indicator of secondary antiphospholipid syndrome in individuals diagnosed with SLE [189] . Methemoglobinemia syndromes include the following inflammatory, autoimmune, and infectious diseases: AOSD is a rare systemic autoinflammatory disease, the cause of which is currently unknown [190] . Despite several infectious agents suspected to be causative of the disease due to the similarity of their clinical presentations [191,192] , the cause remains unknown. AOSD is characterized by a high fever with joint pain and a salmon-like yellow macular or maculopapular rash during the fever [193] . Additional clinical manifestations such as myalgia, lymphadenopathy, splenomegaly, and hepatomegaly have been observed. Pertinent laboratory results reveal increased levels of CRP and erythrocyte sedimentation rate, a leukocytosis dominated by neutrophils, anemia, elevated hepatic enzymes, and methemoglobinemia [194] . Methemoglobinemia has been proposed as an adjunctive diagnostic marker for AOSD . Multiple studies have suggested establishing a diagnostic threshold at 1000 ng/mL for this condition [195] . Notably, considerably elevated levels, reaching up to 30,000 ng/mL, have been reported as a frequent finding in affected individuals, with some studies documenting extreme values of up to 250,000 ng/mL [196] . Consequently, while the proposed diagnostic threshold has been set at 1000 ng/mL, the majority of patients typically present with substantially higher levels. Furthermore, in AOSD , ferritin serves as a biomarker for assessing disease activity, particularly following the commencement of treatment and during periods of remission, when ferritin values return to normal [195] . Moreover, a direct relationship has been established between ferritin levels and disease activity [197,198] . In research involving 147 adults diagnosed with Still’s disease, elevated levels of ferritin and CRP were identified as indicators for both mortality and MAS [199] . Given that MAS presents a severe risk in AOSD , monitoring ferritin concentrations is crucial for clinicians to facilitate the prompt diagnosis, treatment, and prevention of this serious complication. Recent investigations examining the role of ferritin in AOSD have expanded our understanding beyond its impacts on disease activity, severity, and complications. It is now posited that ferritin could contribute to disease pathogenesis, particularly in light of research linking ferritin to neocoronaryngitis [200] . This theoretical framework is substantiated by evidence demonstrating ferritin’s capacity to stimulate and augment the secretion of various cytokines. MAS , frequently also recognized as secondary hemophagocytic lymphohistiocytosis (HLH), emerges as a severe immunological complication across various autoimmune disorders, including juvenile arthritis and systemic lupus erythematosus [201] . This condition is distinguished by the swift proliferation and activation of T lymphocytes and macrophages, which exhibit hemophagocytic activity [202] . Often, MAS is either overlooked or identified belatedly within the disease progression due to its clinical manifestations closely resembling those of systemic inflammatory diseases, significantly influencing the elevated rates of morbidity and mortality associated with it [203] . The presentation of MAS is characterized by severe symptoms, including elevated temperatures, dermatological signs such as purpura or petechiae, and swelling [204] . Commonly, this condition affects multiple organs. Respiratory issues, such as breathlessness and coughing, are frequent and in critical cases, can cause respiratory failure. Moreover, issues related to the gastrointestinal and renal systems are noted [205] . Early in the disease progression, neurological manifestations are prevalent in patients suffering from this syndrome [206] . These manifestations can range from meningitis and encephalomyelitis to cerebral hemorrhage. Laboratory analyses often reveal a reduction in total blood cell counts, methemoglobinemia, altered liver function tests, and increased triglyceride levels [207] . Due to the similarity in clinical manifestations between MAS and various autoimmune and inflammatory disorders, a specific set of diagnostic criteria has been developed. Prompt diagnosis and treatment are crucial, as they are potentially life-saving. Ferritin levels represent a fundamental component of these diagnostic criteria. A minimum threshold of 500 ng/mL is considered necessary for diagnosing MAS [203] . However, ferritin concentrations frequently reach 5000 ng/mL or higher. Research has demonstrated that ferritin levels exceeding 1000 ng/mL demonstrate high specificity for MAS diagnosis [208] . Indeed, elevated ferritin levels are essential for diagnosing MAS. For instance, while juvenile idiopathic arthritis (JIA) frequently coincides with MAS, Ravelli along with a group of specialists [209] formulated diagnostic criteria specifically for MAS when it complicates systemic JIA. Consequently, a ferritin threshold exceeding 684 ng/mL is considered a critical diagnostic criterion. The researchers emphasized the significance of this criterion in facilitating MAS diagnosis and enabling more effective patient inclusion in clinical studies, thereby advancing the evaluation of potential therapeutic interventions. Notably, the previously established diagnostic criteria for MAS were derived from the HLH-2004 diagnostic guidelines [210] . These guidelines specified a ferritin threshold of 500 ng/mL and were primarily implemented for diagnosing primary HLH. The consistent inclusion and significance of ferritin measurement across these various criteria and guidelines underscore the critical importance of ferritin in the diagnostic evaluation and understanding of MAS. cAPS . Antiphospholipid syndrome is a systemic autoimmune condition characterized by the production of autoantibodies targeting platelet phospholipid-binding proteins. This autoimmune response leads to extensive intravascular thrombosis affecting both arteries and veins [211] . Antiphospholipid syndrome can present as primary (occurring independently) or secondary (developing in association with other systemic autoimmune diseases, predominantly SLE) [211] . Antiphospholipid syndrome is diagnosed through the identification of thromboembolic events and the detection of antiphospholipid antibodies, as per established clinical and laboratory criteria [212] . A minor subset of individuals diagnosed with antiphospholipid syndrome may progress to a severe manifestation known as cAPS [213] . This condition is primarily identified by widespread microvascular thrombosis that precipitates multi-organ failure and is linked to a significant increase in mortality rates [214 ]. Furthermore, elevated serum ferritin levels are observed not only in typical cases of antiphospholipid syndrome but also in its catastrophic variant. Research involving 176 patients with antiphospholipid syndrome [215] revealed that 9% exhibited elevated serum ferritin levels, whereas none of the 98 age- and sex-matched healthy controls showed such elevation. Among those suffering from hyperferritinemia, high ferritin levels correlated with venous thrombosis and cardiac, neurological, and hematological complications. Notably, in this cohort, 71% of the 14 patients with cAPS developed hyperferritinemia. The researchers discovered that ferritin concentrations were considerably elevated in patients with the catastrophic variant of antiphospholipid syndrome compared to those without it (816 ng/mL versus 120 ng/mL). From these results, it was inferred that in the pathogenesis of severe disease, the contribution of ferritin is markedly reduced, particularly in cases exhibiting mild symptoms. Septic Shock , unlike the previously discussed autoimmune and autoinflammatory conditions within the spectrum of ferritin syndrome, embodies the infectious aspect of this syndrome. Recognizing this link is crucial for understanding the subsequent interactions between neocoronary pneumonia and ferritin. Septic shock, a grave and potentially lethal complication of sepsis [216] , is distinguished by insufficient systemic perfusion that results in multiple organ failure [217] . While sepsis represents a response to severe infection, septic shock presents significantly more critical implications. In a study involving 36 children with severe sepsis and infectious shock admitted to the intensive care unit, Garcia et al. [218] identified three distinct subgroups based on ferritin levels: 13 children with ferritin levels below 200 ng/mL, 11 children with levels between 200–500 ng/mL, and 12 children with ferritin levels exceeding 500 ng/mL. As a result, mortality rates were documented at 23%, 9%, and 58%, respectively. It was postulated by the investigators that ferritin concentrations surpassing 500 ng/mL were correlated with substantially elevated mortality when compared to lower measurements. Additionally, the underlying mechanisms and immunomodulatory functions of ferritin in individuals afflicted with sepsis-induced acute kidney injury have been examined in a contemporary investigation [219] . 4.2.10 Relationship between ferritin and infectious diseases Historically, elevated ferritin levels during acute infectious episodes have demonstrated a significant correlation. Research conducted in Scandinavia during the 1970s involving 18 patients afflicted by acute infections revealed an immediate surge in serum ferritin levels following infection onset [220] . This study established that the swift escalation in serum ferritin occurred similarly in patients, irrespective of the infection being viral or bacterial. Moreover, the levels of ferritin and haptoglobin exhibited synchronous fluctuations. Unlike the swift increase in serum ferritin at the disease’s commencement, a decline in ferritin levels was observed only after an interval of up to five weeks. Additionally, another study indicated that in cases of infectious diseases, the period before a decrease in ferritin levels commenced tended to be extended [221] . Augmented ferritin concentrations are likewise observed in bacterial infections. Kawamata et al. [222] analyzed ferritin concentrations in 22 Japanese children suffering from Mycoplasma pneumonia infection. They noted that while ferritin levels were heightened during the acute phase of pulmonary infection, they decreased quickly as the patients recovered. Consequently, the researchers suggested that ferritin concentrations might serve as a reliable measure of disease severity. Moreover, ferritin is suggested as a diagnostic indicator for individuals afflicted with Legionella pneumophila pulmonary infections [223] . Elevated ferritin concentrations have been observed in patients suffering from viral infections, not only bacterial ones. Specifically, in instances of influenza virus infection, serum ferritin levels tend to rise. For instance, among 22 patients infected with the H5N1 influenza virus, six exhibited increased ferritin levels [224] . Furthermore, during the H1N1 epidemic, heightened ferritin levels served as a rapid diagnostic tool for Legionnaires’ disease, aiding in distinguishing between infections by H1N1 and Legionnaires’ disease throughout the influenza season [225] . Additionally, elevated ferritin concentrations have been linked to a worse prognosis in individuals infected with the influenza A virus [226] . In a similar vein, enhanced ferritin levels have been shown to correlate with weaker immune responses to the Hemophilus influenzae vaccine [227] . Apart from influenza, high ferritin levels have been implicated in severe outcomes, such as hemorrhage and mortality, in cases of Ebola hemorrhagic fever [228] . A significant case study reported that two individuals with chikungunya infection developed hyperferritinemia syndrome post-infection, which manifested as AOSD —in these examples, the viral infection induced ferritin elevation, leading to the onset of an autoinflammatory condition [229] . Besides the infectious agents previously discussed, higher serum ferritin levels have also been observed in various other bacterial and viral infections, including the Epstein–Barr virus (EBV), human immunodeficiency virus (HIV), and tuberculosis (TB) [230] . Throughout the outbreaks of Severe Acute Respiratory Syndrome (SARS )[231,232] and Middle East Respiratory Syndrome (MERS) in Saudi Arabia [226,227] , scant data were available concerning ferritin concentrations. Nevertheless, during the initial phase of the SARS crisis, research conducted in Taiwan on the initial 10 individuals diagnosed with the SARS virus indicated elevated ferritin levels in seven patients, varying between 590 ng/mL and 4,984 ng/mL [233] . Moreover, a correlation was observed between increased ferritin levels and deteriorating patient health conditions. 4.2.11 Ferritin and a new type of coronary pneumonia During the global outbreak of neococcal pneumonia, healthcare professionals and researchers noted high ferritin levels in patients during the initial phase. These observations sparked concerns [234] , as high ferritin was associated with negative outcomes [235] . Yet, the underlying mechanisms linking ferritin to worse prognoses remain largely unexplored and warrant further study. Over time, from a diagnostic perspective, rising ferritin levels have been recognized as indicators of increased disease severity. Furthermore, a significant increase in ferritin, coupled with lymphopenia, diminished numbers and activity of NK cells, abnormal liver function, and coagulation anomalies, prompted speculations which eventually led to a consensus. Researchers proposed that neocoronaryngitis might be classified as a new type of methemoglobinemia syndrome [236] . Notably, severe cases of neocoronary pneumonia exhibiting similarities with hyperferritinemic conditions such as Systemic Inflammatory Response Syndrome (SIRS) and Acute Respiratory Disease Syndrome (ARDS) further support this hypothesis [237,238] . Similarities between methemoglobinemic syndrome and its associated complications include elevated serum ferritin levels and critical hyperinflammation, which ultimately precipitates multi-organ failure [236] . Regarding neocoronary pneumonia, its grave outcomes are attributed to two primary pathogenic elements: the direct effects of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus and the host’s immune-inflammatory reactions [239] . Essentially, ferritin serves multiple functions in evaluating both the prognosis and the severity of neocoronary pneumonia. Initially, ferritin acts as an acute phase reactant, with heightened levels observed in initial cases as part of clinical reports, coinciding with reduced lymphocyte numbers and increased CRP levels [240,241] . Moreover, ferritin functions as an indicator of the disease’s severity. During the pandemic, a marked association was noted between heightened ferritin concentrations and increased severity of neococcal pneumonia, with significantly elevated ferritin measurements in severe cases compared to milder instances (2800 ng/mL versus 708 ng/mL). Additionally, in Italian research, high ferritin levels were linked with a greater risk of ARDS in afflicted individuals [242] . Lastly, ferritin also serves as a prognostic marker, with studies indicating that patients suffering from neocoronary pneumonia with elevated ferritin levels experienced prolonged viral clearance and extended hospitalizations [243] . Another study also reported similar findings, demonstrating a link between increased ferritin levels and higher in-hospital mortality as well as dependence on invasive ventilators [244] . Furthermore, several investigations have assessed the viability of targeting ferritin for therapeutic purposes [245] , which might be relevant to the treatment of neocoronaryngitis. A cohort of researchers has explored iron depletion therapy as a viable intervention for individuals suffering from neocoronaryngitis, given the harmful impact of excess iron and the associated elevated levels of ferritin [246] . 5. Ferritin in biomedical engineering Ferritin, prevalent across a range of organisms, is crucial in iron-level regulation, as it stores and releases iron ions [247] . Ferritin is recognized for its advantageous biosafety characteristics, along with the rapid dispersal and effective sustained-release pharmacokinetic properties of its nanoparticles. Moreover, the substantial surface-to-volume ratio of 24 monomeric subunits, coupled with its disassembly and reorganization capacity, supports diverse modifications of both the surface and internal cage through chemical and genetic methods. Ferritin’s hollow spherical configuration, which inherently encapsulates iron ions, has been utilized by researchers in various biotherapeutic applications [248] . Recently, encapsulation of drugs and reagents by ferritin has garnered significant academic attention. This work primarily focuses on loading chemotherapeutic agents, genes, fluorescent molecules, and diverse peptides onto ferritin surfaces. Enhancing the drug-loading efficiency remains a critical challenge across all delivery systems, yet numerous strategies have been devised to incorporate water-insoluble drugs into ferritin. Furthermore, ferritin’s unique triple-symmetry axis facilitates the correct conformational display of antigens, distinguishing it from other nanoparticles [249] . Subsequently, we will discuss the roles of ferritin in therapeutic applications, its use in imaging and diagnostics, its potential in immunotherapy vaccines, and the ongoing and forthcoming clinical trials involving ferritin-based therapies. Fig.5 Ferritin applications in drug delivery, biomolecular imaging, and immunovaccines. 5.1. Ferritin in drug delivery Ferritin’s shell–core configuration can encapsulate various substances, typically facilitated by mineral pores on its exterior or through pH-triggered disassembly and reassembly of its nanocages. Researchers have explored its application in anticancer treatments extensively, most notably using it to transport chemotherapeutic agents directly to tumor sites. This approach generally curtails tumor expansion, exhibits favorable pharmacokinetic characteristics, and diminishes side effects relative to unencapsulated drugs in both laboratory and animal models. These outcomes suggest significant advancements in employing ferritin nanocages for drug delivery in cancer treatment. Adriamycin encapsulation in ferritin has demonstrated effective tumor growth inhibition across various murine cancer model groups. This formulation preferentially targets tumor cells overexpressing transferrin receptor 1 (TfR1), achieving internalization levels 10× those observed with free adriamycin. Additionally, the ferritin-based encapsulation of paclitaxel induced significant apoptosis in MDAMB231 breast cancer cells in an in vivo model [250] . The investigation focused on the delivery of insoluble drugs through ferritin, with particular emphasis on targeting tumor cells to mitigate the side effects of this chemotherapeutic agent. Additionally, ferritin-encapsulated gemcitabine was used concurrently with photothermal therapy, demonstrating efficacy as an adjunctive treatment in a breast cancer model [250] . The incorporation of cisplatin into ferritin facilitated its effective delivery, enhancing the therapeutic efficacy of anticancer treatments in an advanced refractory melanoma model [251] . Adriamycin-loaded ferritin also displayed the phagocytosis-inducing peptide SIRPα for intrinsic vaccination effects [252] . Concurrent administration of SIRPα and adriamycin, which induces immunogenic cell death, effectively suppressed tumor growth in a melanoma model and enhanced re-kinetic peptides anti-tumor activity in another cancer model by initiating effector CD8+ T cell activation. This research aimed to induce the exposure of cancer cell neoantigens to the host immune system, facilitating the continuous proliferation of anti-tumor T cells. This resulted in a notably promising and efficacious therapeutic method. Besides the research previously discussed, ferritin has been applied in various additional contexts. For instance, Seo et al. [253,254] developed a thrombolytic version of ferritin that incorporates a multivalent thrombus-targeting peptide along with a fibrinolytic enzyme, intended for concurrent use with chemotherapy treatments. Similarly, Lee et al. [255] employed both γ-carboxyglutamate protein C (PCGla) and a thrombin receptor agonist peptide in an experimental therapy for acute inflammatory sepsis using a live mouse model. Fig. 6 Targeted delivery of ferritin.(a) The CT-Fn/Met system, featuring cartilage-targeting peptides engineered on its surface and encapsulated metformin (Met), which selectively targets and penetrates chondrocytes, thereby extending IA retention and enhancing OA efficacy. Reproduced from Ref. [256] with permission from Elsevier. (b) Targeted paclitaxel delivery utilizing ferritin heavy chain nanocages for glioma treatment applications. Reprinted from Ref. [257] with permission from Elsevier. (c)Intrinsically tumor-targeted mouse Ferritin nanocages simultaneously delivering GPX4 and FSP1 inhibitors to achieve synergistic iron-death mediated immunotherapeutic effects. (d) A ferritin-based drug delivery platform: hybrid nanocarriers engineered for vascular immunotargeting. Reprinted from Ref. [258] with permission from Elsevier. (e)Spontaneous and high-efficiency incorporation of multiple therapeutic agents into ferritin nanocages through partial opening of ferritin’s hydrophobic channels. The resultant drug-Fe secondary complexes accumulate actively and stably within these modified ferritin structures and are subsequently delivered intracellularly in a pH-responsive manner, facilitated by ferritin’s inherent cell-targeting capabilities. Reprinted from Ref. [259] with permission from John Wiley and Sons Ltd. 5.2 Ferritin in biomolecular imaging Owing to their readily adaptable characteristics, ferritin nanocages are utilized to formulate diagnostic agents for various imaging modalities, including computed tomography and MRI. These nanocages can be concurrently doped or coated with fluorescent molecules and targeting peptides, facilitating specific disease biomarker identification [260] . Zhao et al. [261] engineered magnetic ferritin probes combining iron oxide with 125I radionuclides on the ferritin exterior, facilitating dual-mode tumor imaging. Huang et al. [262] constructed ferritin-based probes incorporating the near-infrared dye IR820, which improves fluorescence and supports combined photoacoustic and photothermal treatments, enhancing imaging contrast. Similarly, Crich et al. [263] created gadolinium-doped ferritin for MRI imaging, aimed at marking tumor endothelial cells. Lee et al. [264] embedded commonly utilized fluorescent molecules like red fluorescent protein into ferritin, targeting tumor-specific antigens for delivery to lymph nodes in a rodent model. Lin et al. [265] designed hybrid ferritin probes for specific near-infrared fluorescence imaging of tumor cells. Likewise, Sitia et al. [266] formulated indocyanine green-enhanced ferritin for tumor-specific imaging, demonstrating its potential in fluorescence imaging-guided oncological surgery. Additionally, fluorescent Cy5.5 was integrated into magnetic ferritin constructs to target vascular macrophages for in vivo inflammation imaging applications [267] . Consequently, ferritin represents a versatile platform capable of targeting specific cellular populations and biomarkers. Fig. 7 Ferritin imaging. (a) Bioengineered H-Ferritin nanocages designed for quantitative visualization of vulnerable atherosclerotic plaques. Reproduced from Ref. [268] with permission from American Chemical Society. (b) Schematic of intracerebroventricular (ICV) injection, stereotactic surgery of CSF-brain barrier and CSF-blood barrier. apoferritin encapsulated in Dy complex permeates CSF-brain and CSF-blood barriers and function as MRI T2 contrast agent vs. non-permeable Resovist® Reprinted from Ref. [269] with permission from Elsevier. (c) Potential clinical application of gold-deoxyprotein nanocages coupled with 2-amino-2-deoxy-glucose in breast cancer cell imaging. Reprinted from Ref. [270] with permission from Springer Berlin Heidelberg. 5.3 Ferritin vaccines in immunotherapy Recently, ferritin-based vaccines have garnered research attention owing to their efficacy and safety [271] . Attempts to create more immunogenic and safer vaccines persist, as traditional vaccines, which often include inactivated viruses or microorganisms, pose reactivation risks [272] . Ferritin surfaces provide a diverse antigenic display, featuring a consistent presentation of 24 epitopes and the uniformity, thermal resilience, and pH stability inherent to ferritin nanocages. Moreover, particle-based peptide delivery has demonstrated greater efficacy than soluble-peptide delivery [273] . The dimensional characteristics (10–12 nm) of ferritin nanocages facilitate their internalization by dendritic cells, enabling lymph node migration and the subsequent enhancement of both cellular and humoral immune responses. With these significant benefits, ferritin-based vaccines have shown exceptional effectiveness not only in treating infectious diseases but also in developing vaccines for cancer and autoimmune conditions. Presently, ferritin-based vaccines targeting diseases such as influenza, SARS-CoV-2, and EBV are available, with some undergoing Phase I clinical trials [272,274] . These vaccines have demonstrated biocompatibility and immunogenicity, and are notably devoid of severe adverse effects. Nevertheless, ferritin-based vaccine development faces significant challenges, including nanoparticle heterogeneity, improper antigen folding, and inter-subunit interactions that result in antigenic interference. As antigens are incorporated into ferritin scaffolds, the self-assembly processes, expression systems, and purification protocols for these vaccine candidates necessitate careful optimization. Currently, early-phase clinical trials are evaluating ferritin-based vaccines. Kanekiyo et al. [275] present a noteworthy example; trimeric hemagglutinin (HA) was attached to ferritin’s three-fold axis, resulting in eight trimeric viral projections. This ferritin-conjugated HA induced a robust immunological response, generating an antibody titer 10× that observed with the inactivated vaccine. These findings have propelled three influenza vaccines into Phase I clinical evaluations (ClinicalTrials.gov IDs NCT03186781, NCT03814720, and NCT04579250) [275,276] . In the initial influenza study (ClinicalTrials.gov ID NCT03186781), investigators documented encouraging outcomes, noting seroconversion frequencies of either 40% or 90%. Additionally, the 50% inhibitory concentrations reached 1×10³ and 3×10³ when applied as monotherapy and in conjunction with an influenza DNA vaccine, respectively [277] . No significant adverse reactions were documented. Subsequent to the ferritin HA vaccine, further vaccines leveraging ferritin have been crafted to combat SARS-CoV-2. While findings remain unpublished, preliminary evidence from a murine model demonstrated the efficacy of a solitary vaccine dose. This vaccine has progressed to Phase I clinical trials (ClinicalTrials.gov ID NCT04784767) [278] . A third ferritin-based vaccine targets EBV and is currently undergoing Phase I clinical trials (ClinicalTrials.gov ID NCT04645147). This vaccine utilizes a ferritin surface modification incorporating EBV glycoprotein 350/220 (gp350). In a mouse model this modified formulation exhibited markedly enhanced neutralizing effectiveness compared to its soluble counterpart [279] . 6. Conclusion and outlook Ferritin nanocarriers present numerous benefits in disease diagnosis and pharmaceutical development, and are actively enhancing research in biotherapeutics, immunotherapy, and vaccines. Owing to its remarkable biocompatibility, ferritin provides extensive opportunities for modification. Its subunit architecture enables the uniform presentation of 24 exterior peptides, achievable through either a single-step genetic alteration or direct chemical coupling. Moreover, the hollow cage structure permits the delivery of a variety of insoluble or cytotoxic drugs through disassembly, reorganization, or mineralization of the surface pores. Ferritin serves as a versatile protein scaffold with significant applications in nanomedicine, particularly in vaccine development. Ferritin nanocages have been employed in three influenza vaccines currently undergoing Phase I clinical trials; notably, one has demonstrated encouraging outcomes. The proven effectiveness of these ferritin-derived vaccines has catalyzed further studies attempting to enhance the formulation of additional vaccines based on ferritin that are currently under clinical evaluation. The potential of ferritin extends beyond vaccine development to include the diagnosis, prevention, and treatment of diseases. Although considerable progress has been made in ferritin-embedded substance preparation methods and applications, several issues remain. First, the embedding efficiency and loading capacity of ferritin require improvement. Artificially designing novel ferritin nanocages with different shapes and properties or preparing protein assemblies to utilize the space between assembly gaps are possible solutions, but the specific application systems must be explored in depth. Second, current studies predominantly concentrate on the preparation methods and pharmaceutical applications of ferritin-embedded substances, and the utilization of ferritin nanocarriers in food nutrition and detection warrants further attention. Finally, ferritin stability in the stomach and the cellular uptake efficiency of the guest molecules require enhancement before ferritin delivery systems can contribute to human nutrition and health in practical clinical applications. 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Keywords biomedical engineering biomolecular imaging drug delivery ferritin Authors Affiliations Weiming Song Changsha Stomatological Hospital View all articles by this author Liming He Changsha Stomatological Hospital View all articles by this author Xiaoyan Xie The Second Xiangya Hospital of Central South University View all articles by this author Beikang Tang The Second Xiangya Hospital of Central South University View all articles by this author Honghui Xie Changsha Stomatological Hospital View all articles by this author Ying Cai Hangzhou Stomatology Hospital View all articles by this author Shuangjiang Li 0009-0004-3392-8582 [email protected] Changsha Stomatological Hospital View all articles by this author Lanjie Lei Zhejiang Shuren University View all articles by this author Metrics & Citations Metrics Article Usage 559 views 296 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Weiming Song, Liming He, Xiaoyan Xie, et al. 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