How Changes in Uric Acid Form Trigger Immune and Metabolic Inflammation and Targeted Treatments

In the context of persistently elevated SUA levels, the homeostasis of intracellular energy metabolism is initially disrupted, with one of the primary targets being the crucial sensor of energy balance—AMP-activated protein kinase (AMPK) (43). Under physiological conditions, cellular energy depletion activates AMPK, which subsequently initiates catabolism to generate energy while inhibiting anabolism to conserve resources (44). However, high levels of SUA may amplify energy stress signaling. Concurrently, SUA-induced oxidative stress may impair full AMPK activation via post-translational modifications, leading to a condition in which activation cues persist but functional AMPK activity remains insufficient. This SUA-related functional disorder leads to the release of mTORC1 inhibition, which is a major regulator of anabolic metabolism. In an environment of energy stress, mTORC1 becomes continuously and abnormally active, driving unnecessary protein and lipid synthesis, which exacerbates the metabolic burden on cells. This results in blocked catabolism and impaired AMPK-dependent autophagy, leading to a failure in cellular autophagy processes (45, 46). Damaged mitochondria cannot be cleared in a timely manner and continue to release mtROS, creating a positive feedback loop of energy depletion and oxidative damage. Ultimately, this process induces cellular aging and apoptosis, while continuously releasing DAMPS and mtROS that activate the NLRP3 inflammasome, resulting in tissue-specific damage (47–49).

In addition to its indirect effects on energy metabolism through AMPK, SUA can directly impact mitochondria, the energy production centers of cells. SUA disrupts the electron transport chain within the mitochondrial inner membrane, leading to decreased electron transport efficiency and increased electron leakage. This results in reduced oxidative phosphorylation efficiency and energy output. Simultaneously, leaked electrons combine with oxygen molecules, causing bursts of mitochondrial-derived ROS, which have become a significant source of oxidative stress in cells (50, 51). In the context of energy perception disorders induced by SUA and mitochondrial dysfunction, when energy perception disorders and mitochondrial damage occur, abnormal energy metabolism and the resultant generation of reactive oxygen species activate a series of stress-sensitive signaling pathways, including the c-Jun N-terminal kinase, protein kinase C, and IKK β/NF-κB pathways (52, 53). These pathways share a common feature: they can phosphorylate a key protein in the insulin signaling pathway, insulin receptor substrate 1, at inappropriate serine/threonine sites. The serine phosphorylation of IRS-1 prevents its normal activation by the insulin receptor, hindering its binding to the downstream effector phosphatidylinositol 3 kinase. This results in severe inhibition of PI3K Akt pathway, which is the core axis of insulin signaling. Concurrently, metabolic disorders lead to an imbalance in lipid synthesis and degradation within cells, causing the accumulation of harmful lipid intermediates that result in lipotoxicity and further damage to insulin signaling (47, 54, 55).

Building on the previously discussed SUA-induced disturbances in energy metabolism and insulin resistance, the onset and exacerbation of oxidative stress represent a crucial pathological amplification mechanism.

First, under high metabolic stress related to SUA, dysfunctional mitochondria are considered a potential source of sustained ROS generation. The integrity of the electron transport chain is compromised, significantly increasing electron leakage from dysfunctional mitochondria. As a result, these mitochondria shift from being the “energy factory” of cells to becoming the primary pathological source of reactive oxygen species, such as superoxide anion (56, 57).

Second, SUA-induced insulin resistance state activates systemic ROS generation pathways. Hyperinsulinemia, which accompanies insulin resistance, along with early low-grade inflammatory signals, can further stimulate the expression and activation of NADPH oxidase (particularly the NOx subtype) on the cell membrane. This enzyme is induced to express and activate in considerable amounts, catalyzing the reduction of molecular oxygen to produce superoxide anion, thereby establishing a systematic mechanism for ROS production at the cell membrane level (58).

Third, In the context of persistent hyperuricemia-related metabolic disorders, the endogenous antioxidant defense system becomes weakened. The disorder in energy metabolism and the imbalance of redox homeostasis can lead to excessive depletion of crucial endogenous antioxidant substances, such as glutathione, superoxide dismutase, and thioredoxin. This also inhibits the biosynthesis of related antioxidant enzymes, resulting in a significant decline in the inherent ability of cells to scavenge free radicals. Consequently, an unbalanced state arises, characterized by “increased ROS production” and “insufficient ROS clearance,” available population-based and experimental studies suggest a tendency toward elevated intracellular oxidative stress (59–61).

When SUA-induced metabolic stress and oxidative stress are sustained, the inflammatory response is consequently triggered and exacerbated. Excessive ROS serve not only as a direct agent causing damage to biological macromolecules but also as a potent second messenger that activates key pro-inflammatory signaling pathways, such as NF-κB and MAPK, through the oxidative modification of essential signaling proteins (62). Once activated, these transcription factors translocate to the nucleus, initiating the expression of various pro-inflammatory cytokines and chemokines, including TNF-α and IL-6. This response constitutes the “first wave” of the inflammatory signal and leads to the upregulation of transcriptional expression of NLRP3,pro-IL-1β and pro-IL-18, thereby preparing the molecular groundwork for inflammasome assembly.

Oxidative stress, coupled with mtROS and mtDNA released from mitochondrial dysfunction, creates a potent “danger signal” (48, 63, 64). Following the assembly of the inflammasome, caspase-1 is activated through self-cleavage. The activated caspase-1 then cleaves and activates the precursors of IL-1 β and IL-18, transforming them into their mature, biologically active forms, which are subsequently secreted outside the cell. Simultaneously, caspase-1 cleaves gasdermin D (GSDMD), triggering a form of inflammatory programmed cell death known as pyroptosis. This process results in the release of cellular contents and a multitude of inflammatory mediators. Consequently, TNF-α, IL-6, and other inflammatory factors mediated by NF - κB pathway, along with IL-1β, IL-18, and pyroptotic products specifically mediated by the NLRP3 inflammasome, create a synergistic amplification effect within the tissue microenvironment. IL-1 β and other cytokines further activate and recruit immune cells, enhancing NF-κB and other signaling pathways, thereby establishing a self-sustaining positive feedback inflammatory cycle (65–67). Driven by sustained metabolic and oxidative stress, inflammatory signaling may extend beyond intracellular abnormalities and progressively shape the surrounding tissue microenvironment, giving rise to a chronic, low-grade yet potentially amplifying state of “metabolic inflammation.” This persistent inflammatory milieu may create a permissive pathological context for subsequent structural remodeling and functional impairment of target organs.

Persistently elevated SUA in the heart can act as a damage-associated molecular pattern under pathological conditions, recognized by Toll-like receptors (such as TLR4) on the surface of cardiomyocytes and immune cells. This recognition initiates the NF-κB–mediated transcription of inflammatory genes, referred to as the “first signal”. Concurrently, high SUA induces mitochondrial dysfunction, leading to a surge of mitochondrial reactive oxygen species (mtROS). This surge provides the “second signal” necessary for NLRP3 inflammasome assembly. The convergence of these two signals activates the NLRP3 inflammasome, which catalyzes the maturation and release of IL-1β and IL-18. This process persistently activates cardiac fibroblasts and promotes excessive extracellular matrix deposition, contributing to the development of progressive myocardial interstitial fibrosis. Such structural remodeling impairs ventricular diastolic compliance and disrupts the uniformity of electrical conduction, forming the pathological basis for heart failure with preserved ejection fraction (HFpEF) and cardiac arrhythmias (68–71).

In the endothelium of blood vessel walls, long-term high SUA-related ROS attacks significantly increase the expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin on endothelial cells, enhancing lipid permeability. This process also damages the tight junctions between endothelial cells, increases vascular permeability, and reduces the expression of anticoagulant substances while elevating procoagulant substances, creating a procoagulant state. In this environment, the endothelium, characterized by high adhesion molecule expression, aggressively “captures” monocytes from the bloodstream, facilitating their adherence and migration to the endothelium. Low-density lipoprotein (LDL) that infiltrates and accumulates beneath the endothelium undergoes oxidation, transforming into oxidized low-density lipoprotein (ox LDL) due to local high levels of ROS. This oxLDL is then engulfed by macrophages derived from the migrating monocytes, ultimately forming the characteristic foam cells associated with atherosclerosis (72, 73). Sustained oxidative stress and inflammatory cytokine release driven by elevated SUA may upregulate and enhance the expression and activity of matrix metalloproteinases (MMPs) in vascular wall cells, particularly macrophages and vascular smooth muscle cells. MMPs mediate the degradation of collagen and other extracellular matrix components within the fibrous cap, thereby disturbing the dynamic balance of collagen synthesis and degradation that underlies plaque stability.When collagen degradation becomes relatively enhanced and compensatory synthesis—primarily mediated by vascular smooth muscle cells—is insufficient, the structural integrity of the fibrous cap may be compromised. This is characterized by reduced collagen content and diminished mechanical strength, contributing to increased plaque vulnerability.Under such conditions, plaque rupture or superficial erosion may expose thrombogenic components to the circulating blood, triggering platelet adhesion and activation as well as the coagulation cascade, leading to thrombus formation of varying extent. In some cases, thrombi may progress to hemodynamically significant stenosis or even occlusion, which is associated with an increased risk of acute myocardial infarction or ischemic stroke. (68, 74–77).

In the kidneys, metabolically active proximal tubular epithelial cells are particularly vulnerable to energy stress. SUA-induced oxidative damage and ATP depletion result in cell apoptosis and aging. SASP factors and DAMS create a chronic inflammatory microenvironment that continuously recruits and activates macrophages and NLRP3 inflammasomes (78, 79). The cleavage of gsdmd mediated by caspase-1 triggers pyroptosis. The DAMPs released by dying cells further amplify the inflammatory signal, driving myofibroblast activation and collagen deposition, which culminates in tubulointerstitial fibrosis. As fibrosis progresses, nephrons are replaced by scar tissue, leading to a gradual decline in renal function, which represents the core pathological process underlying the development of chronic kidney disease (CKD) (80, 81).

In the liver, persistently elevated SUA under pathological conditions may disturb hepatocellular lipid homeostasis by interfering with energy-sensing pathways and autophagic clearance mechanisms. Under physiological conditions, AMPK regulates key metabolic nodes, including acetyl-CoA carboxylase (ACC), through phosphorylation, thereby suppressing de novo fatty acid synthesis and promoting lipid oxidation. In contrast, under high-SUA–associated stress conditions, available evidence suggests that AMPK signaling may be suppressed or functionally insufficient, shifting ACC-mediated regulation toward a more lipogenic state and contributing to hepatic lipid accumulation.Concurrently, impaired autophagic flux,particularly dysregulated lipophagy,may reduce the efficiency of lipid droplet degradation and clearance, thereby further exacerbating intracellular lipid overload. (82, 83). In the context of metabolic disequilibrium, excessive lipid accumulation and mtROS activate the NLRP3 inflammasome in both hepatocytes and Kupffer cells. This activation is mechanistically linked to pathological changes, including hepatocellular ballooning, cellular injury, and necrosis. As the inflammatory response unfolds, the release of the profibrotic cytokine transforming growth factor-β (TGF-β) promotes the transdifferentiation of hepatic stellate cells into a myofibroblast phenotype. This process leads to excessive deposition of collagen and extracellular matrix, therefore, AMPK–ACC dysregulation and inflammation–fibrosis signaling linked to elevated SUA may constitute one of several mechanisms implicated in the progression from NAFLD to NASH and cirrhosis (50, 84).

SUA-induced inflammation and insulin resistance create a destructive network in key metabolic organs. In the liver, the inhibition of the PI3K/Akt axis increases the activity of glycogen synthase kinase 3 (GSK3), thereby blocking glycogen synthesis. Concurrently, the inhibitory effect of insulin on the transcription factor FoxO1 is diminished, leading to up-regulation of key gluconeogenesis enzymes (PEPCK and G6Pase). This results in hypergluconeogenesis and fasting hyperglycemia (85, 86). At the level of lipid metabolism, insulin resistance diminishes the normal inhibition of mitochondrial fatty acid oxidation, promoting the abnormal synthesis of very low-density lipoprotein and the accumulation of lipid droplets in the liver. This forms the molecular basis for metabolism-related fatty liver disease (87, 88).

In skeletal muscle, decreased Akt activity prevents the glucose transporter GLUT4 from translocating from intracellular vesicles to the cell membrane, significantly reducing glucose uptake (89, 90). At the same time, SUA and ROS can directly damage the mitochondrial electron transport chain complex, decreasing the coupling efficiency of oxidative phosphorylation and ATP synthesis (91). Additionally, the expression of peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1 α) is down-regulated, which weakens mitochondrial biogenesis and autophagy. This leads to mitochondrial dysfunction, a shift in cell energy utilization from high-efficiency oxidation to low-efficiency glycolysis, reduced basic energy consumption, and increased susceptibility to obesity (92). The reduced ability of muscle to oxidize fatty acids allows free fatty acids (FFA) to return to the liver, further promoting liver steatosis and exacerbating systemic lipotoxicity (93).

In adipose tissue, the uptake of SUA by adipocytes can disrupt insulin signaling, inhibit the activity of peroxisome proliferator-activated receptor γ (PPAR γ), and lead to disorders in preadipocyte differentiation disorder, mature adipocyte, as well as hypertrophy and dysfunction in mature adipocytes. This disruption results in an imbalance in adipokine secretion: levels of the insulin-sensitizing and anti-inflammatory factor adiponectin decrease significantly, while pro-inflammatory factors such as leptin, TNF - α and MCP-1 increase. This shift promotes macrophage infiltration and amplifies local chronic inflammation (94–96). Impaired insulin signaling further leads to the disinhibition of hormone-sensitive lipase, resulting in enhanced abnormal basal lipolysis and a continuous overflow of free fatty acids FFA. This “lipid overflow” occurs due to the failure of adipose tissue to store lipids, contributing to hyperlipidemia (97). Excessive FFA then spills into the liver, muscle, and pancreas, driving ectopic lipid deposition, aggravating insulin resistance, and damaging β-cell function. Consequently, adipose tissue becomes a persistent source of chronic low-grade inflammation, which further impairs systemic insulin sensitivity through circulating pro-inflammatory factors (98–100).

These interconnected processes exacerbate metabolic inflammation, leading to systemic metabolic disorders and forming a network of cellular interactions that contribute to SUA-mediated insulin resistance. In metabolic terms, this manifests as hyperinsulinemia, elevated fasting blood glucose, and impaired glucose tolerance. Organically, it is reflected in liver steatosis, muscle mitochondrial dysfunction, adipose tissue inflammation, and decreased energy expenditure. Systemically, it is closely associated with metabolic syndrome, type 2 diabetes, atherosclerosis, hypertension, and other comorbidities. Clinical studies have confirmed a significant positive correlation between serum uric acid levels and insulin resistance indices, indicating that uric acid-lowering therapies can improve insulin sensitivity to some extent. This suggests that SUA-driven metabolic and immune interactions play a critical role in the development of metabolic syndrome.

The unique form of programmed cell death exhibited by neutrophils in response to MSU crystals is known as netosis. This process is characterized by chromatin deconcentration, nuclear membrane rupture, and the formation of neutrophil extracellular traps (NETs) (110).

The core mechanism underlying netosis relies on ROS production mediated by NADPH oxidase. MSU crystals detect exogenous purine stimulation by activating purinergic receptors, which initiates the Raf/MEK/ERK signaling cascade. The phosphorylation of ERK facilitates the assembly and activation of NADPH oxidase (NOX2), leading to an oxidative burst. The ROS generated by NOX2 acts as both a signaling and effector molecule involved in NET formation. ROS promote the nuclear entry of azurol granulosa protein (NE, MPO) and activate PAD4, resulting in histone citrullination (h3cit) and chromatin de-aggregation. Subsequently, the nuclear membrane ruptures, and DNA is expelled, forming a net structure (111, 112). Concurrently, excessive ROS activate the necrotic signaling pathway involving RIPK3 and MLKL. RIPK3 promotes the phosphorylation of MLKL, leading to its insertion into the cell membrane and nuclear membrane, which creates membrane pores and accelerates chromatin leakage, thereby amplifying netosis (113–115).

Besides the classic oxidative stress pathways, studies indicate that MSU crystals can also directly induce histone citrullination and NET formation through the TAK1/SYK/PAD4 axis or by directly activating the NF-κB pathway, thereby bypassing the classic ROS burst (110, 112). These ROS-independent pathways may become more prominent in chronic or low-grade inflammatory states. Together with the classical oxidative stress pathway, they help sustain the level of NETs in the inflammatory environment.

MSU crystals can activate the non-classical inflammasome pathway through TLR4 and other receptors. This activation leads to the activation of caspase-11, which cleaves GSDMD. The resulting GSDMD N-terminal fragment is responsible for membrane perforation. Additionally, GSDMD-N can specifically target the mitochondrial membrane, causing a collapse of the mitochondrial membrane potential and the release of mitochondrial DNA (mtDNA). As a potent damage-associated molecular pattern, the released mtDNA can further amplify the inflammatory signal and serve as a structural component of neutrophil extracellular traps (NETs), thus creating a self-amplifying loop of netosis (116, 117). When combined with the classical inflammasome pathway in the innate immune response, this process constructs a positive feedback inflammatory cycle that continuously activates inflammasome pathways.

Autophagy, as a key regulatory mechanism of inflammation, plays a complex role as a “bidirectional regulator” in MSU crystal-induced netosis (118, 119). In the early stages of netosis, MSU crystals can be upregulated by the Nfil3/Redd1 signaling axis or through the inhibition of Atg7, a key protein in autophagy. Activated Atg7 and the transcription factor p53 translocate to the nucleus, where they directly upregulate the expression of peptidyl arginine deiminase 4. PAD4 catalyzes the citrullination of the arginine residue on histone H3, facilitating chromatin depolymerization and creating conditions for the release of NETs. However, evidence also suggests that autophagy can have negative effects under certain conditions. Firstly, it can degrade key effector molecules of netosis and break down granular proteins such as neutrophil elastase through the autophagy-lysosome pathway, thereby weakening NET formation. Secondly, autophagy can promote the dissipation of inflammation and limit NET accumulation by enhancing the phagocytosis and clearance of formed NETs by macrophages, helping to prevent excessive tissue damage (119, 120).

In the late stages of an acute gout attack, a large number of NETs aggregate to form AggNETs (aggregated NETs). These dense aggregates not only serve as physical barriers but also play an active role in “inflammatory clearance” (121, 122). The reticular structure of AggNETs can physically capture MSU crystals, reducing their direct contact with immune cells. Additionally, AggNETs are rich in neutrophil serine protease, which can degrade pro-inflammatory factors such as IL-1 β and TNF - α, thereby attenuating the inflammatory cascade (123, 124). The formation of AggNETs signifies a shift in inflammation from amplification to resolution, providing a crucial cytological basis for the self-limitation of gout. In conclusion, NETs induced by MSU crystals exhibit dual pathological functions in gouty arthritis.

Xanthine oxidase is the key rate-limiting enzyme in uric acid production. XOR inhibitors reduce SUA levels by decreasing uric acid synthesis, making them one of the established strategies for lowering uric acid (141). Febuxostat, a selective non-purine XOR inhibitor, is safer for patients with impaired renal function. It significantly lowers blood uric acid levels and downregulates the expression of NLRP3 and IL-1 β, but these anti-inflammatory effects may be secondary consequences of reduced uric acid load, rather than their primary therapeutic target (142). Tigulostat, a new XOR inhibitor, has shown a dose-dependent reduction in uric acid during phase II/III clinical trials, with a curative effect comparable to existing medications and excellent tolerance (143).

An abnormality in uric acid excretion constitutes a significant mechanism underlying hyperuricemia. Inhibitors of URAT1 decrease SUA levels by obstructing the reabsorption of uric acid within the proximal tubule, consequently enhancing uric acid excretion. Benzbromarone and probenecid inhibit URAT1-mediated reabsorption in the proximal convoluted tubules, thereby increasing uric acid excretion (144). Additionally, novel URAT1 selective inhibitors, such as lesinurad and dotinurad, offer higher selectivity and fewer drug interactions. These are often combined with XOR inhibitors to achieve a dual mechanism for uric acid reduction, its clinical benefits stem from the improvement of uric acid homeostasis (145).

Metformin primarily exerts its pharmacological effects by activating AMPK and suppressing hepatic gluconeogenesis, thereby restoring glucose metabolic homeostasis. At the mechanistic level, AMPK activation may secondarily influence lipid metabolism, mitochondrial function, and inflammatory signaling pathways, potentially ameliorating pathological states associated with hyperuricemia. However, much of the evidence supporting these anti-inflammatory effects derives from mechanistic and preclinical studies, and their direct relevance in the setting of hyperuricemia-associated inflammation remains to be established through robust clinical investigation. (80, 146, 147). Accordingly, the anti-inflammatory benefits of metformin are more appropriately regarded as downstream or indirect consequences of metabolic modulation rather than its primary therapeutic target.

Pioglitazone, a classic PPAR γ agonist, improves insulin sensitivity and alleviates systemic lipotoxicity by promoting adipocyte differentiation, enhancing adiponectin secretion, and reducing the expression of TNF - α and MCP-1 (148). Animal and clinical studies indicate that pioglitazone not only enhances insulin resistance and glucose metabolism but also lowers serum uric acid levels, reduces endothelial dysfunction, and mitigates inflammatory responses, providing dual benefits for patients with hyperuricemia or metabolic syndrome (149, 150). However, these benefits are more plausibly interpreted as downstream consequences of improved metabolic and inflammatory milieus, rather than as effects directly targeting uric acid metabolism.In addition, these medications can cause adverse reactions such as water and sodium retention and weight gain, necessitating careful consideration of the patient’s cardiac function status.

Traditional treatments like non-steroidal anti-inflammatory drugs (NSAIDs) and Colchicine can inhibit upstream signal amplification; however, their mechanisms of action do not directly target uric acid or MSU crystals. NSAIDs work by reducing the production of prostaglandin E2 and thromboxane through the inhibition of cyclooxygenase (COX-1/2), which in turn decreases vascular permeability and the pain response induced by inflammatory mediators (151). Colchicine, a classical microtubule inhibitor, binds to tubulin and blocks microtubule polymerization. This action inhibits chemotaxis, phagocytosis, and degranulation of neutrophils, effectively blocking the amplification of inflammation caused by lens and reducing the release of IL-1 β. By inhibiting the signaling axis of the P2X7 receptor and the NLRP3 inflammasome, colchicine can terminate the inflammatory response at the intracellular level. The inhibition of the P2X7–NLRP3–IL-1β axis should be viewed as a consequence of regulating the cytoskeleton and signal transduction, rather than as a direct inhibition of inflammasome assembly (152, 153). Accordingly, within the conceptual framework of this review, colchicine is best characterized as an anti-inflammatory modulator.

In cases of refractory or recurrent gout, biological agents targeting IL-1 β—the final effector molecule of the NLRP3 inflammasome—have demonstrated significant efficacy. Canakinumab an Firsekibart, a humanized IL-1 β monoclonal antibody, specifically binds to IL-1 β, blocking its interaction with receptors and thereby inhibiting IL-1 β mediated inflammatory signals. Anakinra, an IL-1 receptor antagonist, competitively inhibits the binding of IL-1 α/β to IL-1R1, providing rapid control of the inflammatory response. This makes it an important option for patients with refractory or frequently recurrent gout, although it still represents a downstream intervention (154, 155). Recently, a series of small molecule drugs that directly inhibit the assembly of the NLRP3 complex have been developed. Mcc950 (cp-456773) is the first compound confirmed to have a highly selective inhibitory effect, as it can directly block ATP hydrolysis and the conformational change of NLRP3, thus inhibiting its activation at the source (156). Meanwhile, dapansutrile (olt1177) administered orally, has shown good safety and an anti-inflammatory trend, although it has not yet been approved for the treatment of gout (157). Arhalofenate exerts dual urate-lowering and anti-inflammatory effects in gout by targeting both metabolic and inflammatory pathways. Mechanistically, it activates AMPK signaling in macrophages to suppress MSU crystal-induced inflammatory responses, while inhibiting renal urate reabsorption transporters to reduce serum urate levels, thereby decreasing gout flare risk and acute inflammation (158). In summary, the treatment of gout is evolving from traditional “broad-spectrum anti-inflammatory” approaches to a new phase of “precise inhibition of inflammatory pathways.” Future treatment for gout will likely shift from merely controlling symptoms to addressing the underlying pathological intervention.