Gouty arthritis (GA) is a form of inflammatory arthritis caused by abnormalities in purine metabolism and/or impaired renal excretion of uric acid, resulting in persistent hyperuricemia and deposition of monosodium urate (MSU) crystals in joint spaces and periarticular tissues. GA is classified as a metabolic rheumatic disorder (1)(2)(3). Epidemiological data show a global prevalence of approximately 1-4% and an incidence of 0.1-0.3%, with a male-to-female ratio ranging from 3:1 to 10:1; notably, its prevalence continues to rise worldwide (4,5). Notably, driven by multiple factors-including the accelerating pace of global population aging, the widespread adoption of high-purine (purine-rich), high-fat diets, and the rising prevalence of metabolic syndrome-the overall incidence of gout continues to rise; it has thus become a significant metabolic disease burden that cannot be ignored in the global public health field (6). As the disease progresses with recurrent flares, patients often develop comorbidities such as diabetes, chronic kidney disease, and cardiovascular complications. Accumulated MSU crystals can further induce joint destruction, bone erosion, deformity, and longterm disability, markedly diminishing quality of life (7). Current therapeutic strategies primarily aim to reduce serum uric acid levels and suppress inflammation, utilizing agents such as colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids. However, these treatments are constrained by limited efficacy, frequent relapses, and notable adverse effects, underscoring the need to investigate novel pathogenic mechanisms and develop more effective therapeutic approaches (8,9). Specifically, in clinical practice, existing medications often prove ineffective for some patients with refractory gouty arthritis, failing to adequately control joint inflammation flare-ups and disease progression. For GA patients with concomitant chronic kidney disease, drugs like nonsteroidal anti-inflammatory drugs (NSAIDs) carry clear contraindications, while medications such as colchicine require strict dose adjustments, significantly limiting treatment options. Additionally, elderly GA patients, due to declining physiological functions and frequent comorbidities, generally exhibit poor tolerance to existing medications. They are prone to adverse reactions such as gastrointestinal disturbances and hepatic/renal impairment, further exacerbating treatment challenges (10).In recent years, ferroptosis has emerged as a novel form of programmed cell death and has attracted substantial attention for its distinct biological characteristics. Defined as an iron-dependent process driven by excessive lipid peroxidation, ferroptosis differs fundamentally from classical cell death modalities such as apoptosis, necrosis, and pyroptosis. Its key molecular features include dysregulated iron metabolism, inactivation of glutathione peroxidase 4 (GPX4), and accumulation of lipid peroxide, ultimately causing oxidative damage to cellular membranes and cell death (11)(12)(13). Morphologically, ferroptotic cells exhibit shrunken mitochondria, increased membrane density, reduced or absent cristae, and outer mitochondrial membrane rupture, while preserving overall plasma membrane integrity, normal nuclear size, and absence of chromatin condensation. Immunologically, ferroptosis is often accompanied by pronounced proinflammatory responses (14)(15)(16)(17). Increasing evidence indicates that ferroptosis not only participates in various pathological processes such as tumors, neurodegenerative diseases, and cardiovascular diseases (18)(19)(20), but is also closely associated with multiple inflammatory and autoimmune diseases including osteoarthritis, rheumatoid arthritis, and systemic lupus erythematosus (21)(22)(23)(24). Notably, a study has demonstrated a positive correlation between systemic iron levels and the frequency of GA flares (25). Experimental findings further reveal that iron supplementation aggravates synovial inflammation in rat models of arthritis (26), while iron chelation therapy reduces inflammatory responses by lowering iron ion levels (27). These observations collectively suggest that ferroptosis may be intimately involved in GA pathogenesis. Despite these associations, the precise mechanisms linking ferroptosis to GA remain insufficiently understood. This review summarizes the molecular regulatory networks governing ferroptosis and explores its potential pathological role in GA. By providing deeper insight into the underlying disease mechanisms, it offers a theoretical basis for the development of ferroptosis-targeted therapeutic strategies, which may hold significant clinical potential for GA management (28)(29)(30). Therefore, ferroptosis represents a promising emerging target for future GA therapy.2.1 Sources, functions, storage, and conversion forms of iron Iron is an essential trace element required for numerous physiological processes in the human body, with a total content of approximately 4-5 grams in healthy adults. It plays a key role in cellular proliferation and growth, particularly in erythrocyte maturation and functions as a vital cofactor for various metabolic enzymes involved in oxygen transport, DNA synthesis, and energy metabolism (31)(32)(33)(34). The human body ingests and absorbs 1-2 mg of iron daily through diet to maintain homeostasis. Dietary iron is present primarily in the forms of Fe² + and Fe³ + , and its metabolism involves four major steps: absorption, transport, storage, and utilization. The central regulatory mechanism ensures precise control of iron uptake, release from storage sites, mobilization for metabolic needs, and limited excretion, thereby maintaining stable intracellular iron levels and preventing iron overload, which can otherwise trigger oxidative stress and cellular damage (35). Dietary iron exists in two main forms: heme iron derived from animal-based foods and non-heme iron obtained from plant sources. Absorption occurs predominantly in the duodenum and upper jejunum and is tightly regulated by key iron transporters such as divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1). Dietary Fe³ + is initially reduced to Fe² + , after which it is taken up into intestinal epithelial cells via DMT1. A fraction of this absorbed iron is exported into the bloodstream through FPN1, where it binds to transferrin and is subsequently delivered to tissues and organs with iron requirements (36). Another fraction is stored intracellularly in the form of ferritin, particularly within macrophages in the liver, spleen, and bone marrow (37,38). Under conditions of iron deficiency or increased physiological demand, ferritin-bound Fe³ + is mobilized through ferritinophagy, reduced again to Fe² + , and made available for metabolic use. Both iron deficiency and iron overload can significantly disrupt normal physiological functions and contribute to disease development (39,40).Ferroptosis is a distinct form of programmed cell death characterized by the intracellular accumulation of iron ions. Its central mechanism involves iron-driven lipid peroxidation, whereby iron ions participate in Fenton chemistry to generate excessive reactive oxygen species (ROS). These ROS trigger oxidative damage to cellular membranes, disrupt membrane integrity, and impair cellular function, ultimately resulting in cell death (41)(42)(43), (Figure 1). The initiation of ferroptosis requires disruption of iron homeostasis, which is maintained through coordinated regulation of iron uptake, storage, and export. Transferrin receptor 1 (TfR1) is responsible for importing extracellular iron into cells, ferritin acts as the main intracellular iron reservoir, and ferroportin (FPN), the only known iron exporter regulated by hepcidin, controls iron efflux. Disturbances in any of these processes can result in iron overload, forming a key driving force for ferroptosis (44,45). Abnormal iron uptake is primarily characterized by excessive expression of transferrin receptor 1 (TfR1). Pathological conditions such as inflammation and hypoxia activate transcription factors including HIF-1a and NF-kB, which upregulate TfR1 and thereby increase endocytosis of Fe³ + . After endocytosis, Fe³ + is reduced to Fe² + and transported into the labile iron pool (LIP) via divalent metal transporter 1 (DMT1). The elevated Fe² + pool provides substrates for Fenton chemistry and enhances lipoxygenase (LOX)-mediated oxidation of polyunsaturated fatty acids (PUFAs) to generate lipid hydroperoxides (LOOH) (46)(47)(48). Dysregulated iron storage further contributes to intracellular Fe² + accumulation through enhanced release and reduced synthesis of ferritin. The autophagy receptor NCOA4 promotes ferritin degradation via ferritinophagy, liberating Fe² + into the cytosol. Concurrently, oxidative stress inactivates iron regulatory proteins (IRPs) and damages ribosomal function, collectively impairing ferritin synthesis and intensifying iron overload (49)(50)(51). Impaired iron export also aggravates pathological iron retention. Chronic inflammatory states, activation of the BMP-SMAD signaling pathway, or mutations in FPN can cause excessive hepcidin production or increased FPN binding to ferritin. These events accelerate FPN internalization and degradation, thereby limiting iron efflux (52). These three factors synergistically form an "iron accumulationoxidative stress" positive feedback loop. ROS further suppress FPN function, promoting the conversion of LOOH into toxic lipid Schematic Overview of the Molecular mechanisms underlying ferroptosis. System Xc -facilitates cystine import, supporting glutathione (GSH) synthesis, which in turn enables glutathione peroxidase 4 (GPX4) to detoxify lipid reactive oxygen species (ROS). In parallel, the FSP1-coenzyme Q10 (CoQ10) axis provides an additional defense by directly scavenging lipid radicals. Iron homeostasis also plays a central role: transferrin (Tf)-transferrin receptor 1 (TfR1) signaling promotes cellular iron uptake, while iron overload enhances oxidative stress through Fenton reactions and NCOA4mediated ferritinophagy. Polyunsaturated fatty acids (PUFAs) are esterified into phospholipids (PUFA-PL), which undergo oxidation to phospholipid hydroperoxides (PL-PUFA-OOH), serving as key executors of ferroptosis. Transcriptional regulators modulate these processes, with p53 suppressing SLC7A11 to reduce antioxidant capacity, whereas NRF2 protects against ferroptosis by regulating iron metabolism and GSH synthesis. The combined effects of GPX4 inhibition, excessive iron accumulation, and cysteine depletion converge to amplify lipid peroxidation, ultimately driving ferroptotic cell death.aldehydes that disrupt cell membrane integrity, ultimately triggering ferroptosis (53).Lipid peroxidation is a central execution step in ferroptosis and is regulated through multiple interconnected mechanisms that directly determine cell fate. Polyunsaturated fatty acids (PUFAs) incorporated into membrane phospholipids provide abundant substrates for oxidative reactions. When intracellular free iron catalyzes the generation of reactive oxygen species (ROS) through the Fenton reaction, a chain reaction of PUFA lipid peroxidation is initiated. The primary oxidation products, such as and disrupt membrane and increase ultimately membrane major lipid and In the pathway, the oxidation of to generate such as and activation significantly enhances to ferroptosis. The free including and such as and species that further damage membranes lipid peroxidation through the glutathione peroxidase 4 (GPX4) GPX4 GSH as a to lipid hydroperoxides into thereby oxidative When GPX4 is or GSH levels are lipid to ferroptotic cell death In to the antioxidant pathway, the provides an mechanism against lipid of this and significantly cellular to ferroptosis As lipid peroxidation its products, such as and cell death signaling by forming with proteins and These impair mitochondrial and functions and activate including NRF2 and signaling ferroptosis is driven by the combined effects of iron-dependent and of antioxidant defense in lipid peroxidation and cell Xc a is essential for GSH synthesis. By the uptake of extracellular it intracellular GSH levels and the antioxidant of of System Xc intracellular cystine GSH synthesis, GPX4 function, and ultimately promotes lipid peroxidation and ferroptosis factors p53 and distinct regulatory in ferroptosis. p53 can ferroptosis by the expression of thereby System Xc the p53 also additional antioxidant in a that can suppress its a of cellular antioxidant the transcription of numerous including and thereby ferroptosis these classical regulatory mechanisms further the of ferroptosis. 1 reduces Q10 (CoQ10) to its antioxidant which functions as a lipid and ferroptosis of GPX4 the ferroptosis regulatory metabolic and antioxidant providing a for its as a promising therapeutic of GA and its with of GA from disturbances in uric acid metabolism that to the and deposition of MSU crystals within and periarticular tissues. These crystals activate the and inflammatory the key and central in driving MSU crystals activate the signaling promoting and degradation of This process from its it to into the target and induce transcription of proinflammatory such as and with inflammatory including Concurrently, MSU with cell proteins like and to activate activation through the to further activation of and of inflammatory thereby to the initiation or of GA inflammatory also plays a role by directly MSU crystals in tissues. in an after which the to the This subsequently the maturation and of and the inflammatory of GA. the to form the processes and into thereby inflammatory In to also its This the plasma promotes cell and further inflammation in GA the of gouty arthritis and inflammatory cells release levels of extracellular through membrane or binds to the cell As an of can be directly or by MSU forms membrane that + and + of which are key for This promotes the maturation and of and thereby or exacerbating inflammatory flares in (Figure is an inflammatory joint disease that to hyperuricemia hyperuricemia and gout are often as conditions to of evidence that the iron content in these foods may also contribute to disease body iron is by and foods in heme including and major to iron overload, in has that disturbances in iron metabolism are closely involved in the development of hyperuricemia and with iron from high-purine foods as a potential A study a positive between serum ferritin and the prevalence of as as a correlation with serum uric acid levels (25). with these a study in demonstrated that serum ferritin, and transferrin receptor levels are associated with the of hyperuricemia of serum iron including ferritin, transferrin and that iron overload is to an increased incidence of iron overload significantly the of hyperuricemia and gout by serum uric acid levels metabolism plays an role in the development of GA. Its pathogenic effects of inflammatory of joint and of uric acid processes, thereby insight into potential therapeutic observations show that patients with gout significantly elevated iron in synovial and periarticular that iron overload may inflammation and contribute to damage demonstrated in an that iron iron accumulation and to a substantial in and with control that iron elevated serum or iron the production of ROS through the Fenton reaction, which the a central of ROS also enhances the of and macrophages to MSU crystals in the of iron resulting in mechanisms in of autoimmune and a of activation In the of joint iron overload a lipid cell death in synovial cells and This to the release of of and of the inflammatory a process also in and In to uric acid iron ions a significant iron can uric acid synthesis and reduce its thereby accelerating the of MSU Additionally, iron within driven by hepcidin and iron to and clear MSU ultimately the inflammatory As central regulators of iron homeostasis, macrophages are particularly to iron which further aggravates Under conditions of elevated increased uptake via TfR1 and with ferritin degradation, to intracellular iron This accumulation macrophages to ferroptotic cell resulting in the release of such as and These and the of proinflammatory including and These can upregulate TfR1 expression in cells, such as and renal epithelial cells, promoting further iron activation of the and of FPN expression reduce iron an that these and supporting evidence from inflammatory therapeutic strategies such as iron and ferroptosis may inflammatory damage by limiting ferroptosis. hepcidin regulation or heme through agents such as to iron may inflammation in GA. 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In a study gout patients, iron chelation therapy that reduced systemic iron to the required for normal causing in a in the frequency and of gout flares the The therapeutic to result from in enhanced efflux of intracellular Fe² + , of intracellular Fe² + overload, and of ultimately joint inflammation Experimental findings in models provide additional In GA joint tissues significantly increased levels of free and a key of with a pronounced in GSH levels Concurrently, clinical elevated serum ferritin and transferrin levels in GA patients, with GA frequency (25). 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Yan et al. (Mon,) studied this question.