Dual Roles of Free Fatty Acids in Gout Pathogenesis: Inflammatory Drivers and Metabolic Mediators

ABSTRACT

Gout, a prototypical crystal‐induced arthropathy, is characterized by a complex interaction between metabolic dysregulation and inflammatory activation. Although monosodium urate (MSU) crystal deposition remains the central pathognomonic feature, accumulating evidence suggests that free fatty acids (FFAs) play a significant role as co‐modulators in the disease's pathogenesis. This review systematically examines the dual role of FFAs in gout pathophysiology: (1) their pro‐inflammatory effects during gout flares through direct modulation of innate immune responses, and (2) their role as metabolic modulators contributing to disease comorbidities. We explore the molecular mechanisms by which saturated and n‐6 polyunsaturated fatty acids (PUFAs) promote NLRP3 inflammasome activation, ultimately leading to cytokine storm formation and acute inflammatory responses. Paradoxically, short‐chain fatty acids and n‐3 polyunsaturated fatty acids exhibit anti‐inflammatory properties and confer protection against gout flares via distinct immunomodulatory pathways. The review further examines FFA‐mediated metabolic disturbances associated with gout, such as insulin resistance, renal fibrosis, and non‐alcoholic fatty liver disease. Additionally, this review provides novel insights into targeted therapeutic strategies for the adjuvant treatment of gout, including lipid‐targeted therapy, microbiome modulation, and dietary recommendations regarding polyunsaturated fatty acids.

Highlights

1. Free fatty acids (FFAs) exhibit dual inflammatory effects in gout, as saturated and n‐6 polyunsaturated fatty acids promote NLRP3 inflammasome activation and cytokine storms while SCFAs and n‐3 polyunsaturated fatty acids exhibit anti‐inflammatory properties and confer protection against gout flares via distinct immunomodulatory pathways.

2. FFAs also play a mediating role in metabolic disturbances associated with gout, including insulin resistance, renal fibrosis, and non‐alcoholic fatty liver disease.

3. Plant‐based polyunsaturated fatty acids show stronger gout protection than marine sources. Targeted lipid and microbiome modulation offer promising adjuvant management strategies for gout.

1. Introduction

Gout is a metabolic disorder resulting from impaired purine metabolism or diminished uric acid excretion, and it is also a prevalent inflammatory arthritis characterized by sudden flares of excruciating joint pain and swelling. It has evolved from a “disease of kings” to a global health concern, with an incidence rate ranging from 0.6 to 2.9 per 1 000 person‐years worldwide, and the prevalence of gout ranges from 0.68% to 3.9% among the population [1, 2]. This metabolic‐arthritis continuum progresses through distinct phases: Hyperuricemia (HUA), gout flares, intercritical gout, and chronic tophaceous disease [3]. While MSU crystal deposition is necessary for clinical manifestation, its occurrence in only 14% of asymptomatic hyperuricemics suggests a requirement for secondary triggers [4].

The incidence and prevalence of gout are increasing globally, closely linked to the rising epidemic of obesity and metabolic syndrome [5]. Obesity, particularly visceral adiposity (waist circumference > 102 cm), confers a 2.24‐fold increased gout risk (95% CI 1.76–2.86). This association is mediated through hyperleptinemia, insulin resistance, and altered adipokine profiles. Mendelian randomization studies confirm causal links between glycemic traits (β = 0.24, p = 3.2 × 10⁻⁵) and urate levels, highlighting shared genetic architecture [6]. Zhang L et al. performed a genome‐wide cross‐over trait analysis, which clearly demonstrated a shared genetic basis and pleiotropic loci between obesity and gout. This genetic evidence underscores the significant role of obesity in the onset and progression of gout [7]. In a 2018 meta‐analysis, obesity (BMI ≥ 30 kg/m²) was associated with a more than two‐fold increased risk of incident gout (adjusted relative risk 2.24, 95% CI 1.76–2.86) compared with individuals with a BMI < 30 kg/m² [8].

In prolonged overnutrition, men with obesity have higher levels of circulating free fatty acids (FFAs). As the physiologically significant energy substrates released from adipose tissue through lipolysis in response to the body's energy demands, FFAs are now increasingly recognized as potent immunomodulators; excess FFAs are stored in different organs as ectopic fat and produce excess reactive oxygen species (ROS) and pro‐inflammation [9]. A study evaluated the relationship between hyperuricemia and FFA. During gout flares, plasma FFA concentrations were significantly higher than those during intercritical gout (median: 0.60, IQR: 0.26 vs. median: 0.39, IQR: 0.12, p < 0.001), hyperuricemia (median: 0.45, IQR: 0.18, p < 0.001), and normal controls (median: 0.46, IQR: 0.20, p < 0.001) [10]. In a cross‐sectional study, elevated levels of FFAs have also been identified as an independent risk factor for tophus formation, with a serum FFA level of 0.46 mmol/L found to be predictive for the onset of tophus [11]. It is suggested that obesity‐induced elevation in FFAs is likely to play a significant role in the development of gout. This review synthesizes cutting‐edge evidence on FFA‐mediated mechanisms in gout, offering new perspectives on therapeutic targeting.

2. FFA Classification and Metabolic Pathways

Fatty acids (FAs) are carboxylic acids with long saturated or unsaturated aliphatic chains and commonly present in organisms as three major forms: Triglycerides, phospholipids, and cholesterol esters. When FAs are not present in the plasma as esters, they are referred to as non‐esterified FAs or FFAs. There are many kinds of FFAs in the blood, including saturated FAs (SFAs), monounsaturated FAs (MUFAs), polyunsaturated FAs (PUFAs), and others. These FFAs in blood can also be classified based on the carbon chain length of their aliphatic tail: Short‐chain fatty acids (SCFAs) contain fewer than six carbon atoms, medium‐chain fatty acids (MCFAs) comprise six to twelve carbon atoms, and long‐chain fatty acids (LCFAs) consist of twelve or more carbon atoms (Table 1) [12, 13].

TABLE 1.

Structural and functional diversity of FFAs.

Class	Chain length	Major species	Primary Sources	Pro‐inflammatory potential	FFA profiles in Gout
SCFAs	C1–C6	Acetate, propionate	Gut microbiota fermentation	Anti‐inflammatory	Reduced
MCFAs	C6–C12	Caprylate, laurate	Dietary triglycerides	Moderate	Unknown
Saturated LCFAs	≥C12	Palmitate (C16:0), stearate	Adipose lipolysis, de novo synthesis	High (NLRP3 activation)	Elevated
Monounsaturated LCFAs	≥C12	Oleate (C18:1), linoleate	Dietary absorption	Low/Context‐dependent	Elevated
Polyunsaturated LCFAs	≥C12	Omega‐3 fatty acids (such as eicosapentaenoic acid, docosahexaenoic acid)	Dietary absorption	Anti‐inflammatory	Reduced
		Omega‐6 fatty acids (such as arachidonic acid)	Dietary absorption	High	Elevated

Abbreviations: LCFAs, long‐chain fatty acids; MCFAs, medium‐chain fatty acids; NLRP3, NOD‐, LRR‐ and pyrin domain‐containing protein 3; SCFAs, short‐chain fatty acids.

SCFAs (including acetate, propionate) are produced by gut microbial fermentation of indigestible dietary fiber and are also found in fermented foods. MCFAs (such as caprylate, laurate) primarily originate from dietary triglycerides. They are directly absorbed into the bloodstream through intestinal capillaries and transported through the portal vein alongside other absorbed nutrients. LCFAs, including both saturated LCFAs (e.g., palmitate (C16:0), stearate) derived from adipose lipolysis and de novo synthesis, as well as unsaturated LCFAs (e.g., oleate (C18:1), linoleate) absorbed from the diet, are taken up by the perivillus adipose tissue and subsequently reassembled into triglycerides [12]. The circulating pool of FFAs consists of up to 40 distinct molecular species, among which 9 LCFAs constitute over 96% of the total FFAs by molarity [14].

In adipose tissues, FFAs are re‐esterified to form triglycerides (TAGs), which are stored in adipose droplets of adipocytes and subsequently mobilized through lipolysis, i.e., the hydrolysis of TAGs. Albumin in circulation acts as a binding agent for FFAs, which can be taken up by mitochondria‐containing cells from circulating plasma and undergo β‐oxidative metabolism in mitochondria, resulting in the production of carbon dioxide and water in the end. The energy released during β‐oxidation and the citric acid cycle generates significant amounts of ATP, making FFAs an essential energy source for various tissues [13]. In addition to serving as an energy source, FFAs also play crucial roles in receptor signaling and inflammatory responses.

3. FFA Profiles in Gout

In obese individuals, the levels of total SFAs, total MUFAs, and total PUFAs are significantly higher compared to those in normal‐weight individuals. Furthermore, long‐chain FFAs were found to consist of approximately 35% saturated fatty acids and 65% unsaturated fatty acids [15, 16]. Analysis of plasma free fatty acid profiles in gout patients revealed elevated levels of MUFAs (such as oleic acid) and reduced levels of PUFAs (such as arachidonic acids) across various lipid fractions in the plasma [16]. A previous study comparing synovial fluid and serum composition demonstrated significantly higher concentrations of free fatty acids in gout patients compared to those with rheumatoid arthritis (RA) or osteoarthritis (OA) [17]. This elevation was particularly pronounced for SFAs (such as palmitic acid and stearic acid) and MUFAs (such as oleic acid). Additionally, gene polymorphism analysis indicated that single nucleotide polymorphisms (SNPs) located in the elongation of long‐chain‐fatty‐acid‐like family member genes are associated with an increased susceptibility to gout [18]. For polyunsaturated fatty acids, plasma metabolic profiling of patients with acute gout revealed that arachidonic acid metabolites, such as leukotriene B4 (LTB4) and 5‐oxo‐eicosatetraenoic acid (5‐oxo‐ETE), were significantly elevated [19].

Notably, gout patients exhibited a significantly lower abundance of short‐chain fatty acid‐producing bacteria in the intestinal tract, such as butyrate‐ and propionate‐producing bacteria, compared to hyperuricemic individuals [20]. A metagenomic analysis of the gut microbiome revealed that the Enterobacteriaceae family and butyrate‐producing species were reduced in gout patients. Levels of SCFAs were remarkably increased during the intercritical gout compared to the gout flare [21]. Additionally, genes involved in urate degradation and short‐chain fatty acid production were reduced in gout patients, indicating a lower level of short‐chain fatty acids in this patient cohort.

LCFAs circulate while bound to albumin (with 99.97% protein‐bound) and enter cells via CD36 or fatty acid transport proteins (FATPs). CD36, a cell membrane‐associated protein that functions both as a signaling receptor and as a fatty acid transporter, is transcriptionally regulated by peroxisome proliferator‐activated receptor γ (PPARγ), which is a ligand‐activated nuclear receptor, a physiological sensor of FFA oxidation, and is recognized as a functional receptor that governs numerous physiological and pathophysiological processes [22]. During gout flare, it has been confirmed that the expression of CD36 is upregulated in monocytes stimulated by MSU crystals. This upregulation is dependent on PPARγ ligand activation and culminates in the production of proinflammatory cytokines in gout [23].

4. Molecular Mechanisms of Saturated LCFAs‐Induced NLRP3 Inflammasome Activation

Saturated LCFAs, such as palmitic acid, are predominantly involved in modulating key immune‐inflammatory cell populations, including neutrophils, macrophages, and lymphocytes. Research indicates that palmitic acid and stearic acid primarily activate the Toll‐like receptor signaling pathways, thereby initiating inflammatory responses in gout flare [24, 25]. The acute symptoms of arthritis are triggered by the inflammatory response to MSU crystals, primarily mediated by macrophages and neutrophils. It is currently recognized as a prototypical inflammatory disorder characterized by the activation of NOD‐, LRR‐, and pyrin domain‐containing protein 3 (NLRP3) inflammasome and subsequent release of pro‐inflammatory cytokines [26]. Inflammasome engagement can be dissected into two prerequisite steps: Priming and activation. Recent studies have demonstrated that pure MSU crystals do not elicit an inflammatory response and are incapable of activating the NLRP3 inflammasome. Co‐stimulatory factors such as lipid mediators, pro‐inflammatory cytokines, and complement activation are required for this process [2, 26]. The combination of saturated LCFAs, specifically C18.0 and C16:0 fatty acids, with MSU crystals exhibits a potent synergistic effect on the activation of the NLRP3 inflammasome in peripheral blood mononuclear cells (PBMCs) obtained from patients with gout. This synergistic effect is mediated by the recruitment of the adaptor protein apoptosis‐associated speck‐like protein containing CARD (ASC), followed by caspase 1 recruitment, which facilitates the assembly and activation of NLRP3 inflammasomes and initiates the conversion of pro‐IL‐1β to bioactive IL‐1β [27, 28].

The mechanism through which long‐chain fatty acids contribute to the activation of NLRP3 inflammasomes is complex. NLRP3 inflammasomes priming phase encompasses the transcriptional upregulation of all structural components necessary for inflammasome assembly, as well as the synthesis of precursor proteins that serve as substrates for inflammatory caspases. Palmitic acid is a toll‐like receptor agonist that can induce the secretion of inflammatory cytokines by binding to toll‐like receptor (TLR) family members. This, in turn, amplifies the phosphorylation of myeloid differentiation factor 88 (MyD88) and the subsequent phosphorylation of p38 and c‐Jun N‐terminal kinases (JNK) in macrophages, as demonstrated in numerous animal and cell experiments employing specific inhibitors and siRNAs [25, 29, 30, 31]. This phosphorylation event promotes nuclear factor kappa B (NF‐κB) signaling and AP‐1 (c‐Jun) transcription factor activation, leading to the expression of functional NLRP3 inflammasome components [29, 32, 33]. Frommer KW et al. analyzed the effect of FFA on synovial fibroblasts, human chondrocytes, and endothelial cells. Their findings indicated that FFA (both saturated and unsaturated) dose—dependently enhanced the secretion of the pro—inflammatory cytokine in synovial fibroblasts via TLR4 and required extracellular and intracellular access to the TLR4 receptor complex [30].

The assembly of the NLRP3 inflammasome is initiated by MSU, a process that involves potassium efflux through ion channels and mitochondrial perturbations, which lead to the production and cytosolic release of mitochondrial ROS [33]. Subsequently, NLRP3‐activating factors are recruited, facilitating NLRP3 oligomerization and inflammasome assembly. LCFAs transported into mitochondria via CD36 exert multiple regulatory effects on inflammasome activation. Firstly, palmitate and MSU crystals synergistically suppress the expression of Sirt3, a key regulatory enzyme involved in the deacetylation of mitochondrial proteins, thereby promoting mitochondrial oxidative stress and activating the NLRP3 inflammasome [34]. Meanwhile, LCFAs also inhibit the mitochondrial respiratory chain by interfering with electron transport at complexes I and III, thereby increasing electron transport chain (ETC) leakage and promoting superoxide generation. Finally, LCFAs facilitate NLRP3 structural rearrangement, as reactive oxygen species (ROS) can oxidize tyrosine residues of NLRP3 (e.g., Tyr30 and Tyr32), thereby enhancing its interaction with ASC. This process may be modulated by phosphatases such as PTEN [35] (Figure 1).

FIGURE 1.

Proposed pro‐inflammatory mechanism of FFA‐MSU synergy in gout flare. In the phase of gout flare, a robust synergistic effect on the inflammatory response is observed when LCFAs are combined with monosodium urate (MSU) crystals. (1) Saturated LCFAs, such as palmitate, enhance NLRP3 inflammasome priming by augmenting TLR2 or TLR4 signaling. Ligand binding recruits the adaptor protein MyD88, initiating phosphorylation cascades that activate JNK kinases. These events lead to the activation of the transcription factors NF‐κB and AP‐1, resulting in the upregulation of inflammasome components and precursor proteins. Regarding inflammasome activation, stimuli such as MSU crystals induce mitochondrial ROS production, which promotes NLRP3 oxidation and facilitates ASC interaction and inflammasome assembly. (2) n‐6 polyunsaturated fatty acids, such as arachidonic acid, activate the cyclooxygenase and lipoxygenase pathways, stimulating the production of prostaglandins and leukotrienes, which in turn enhance the synthesis of TNF‐α and IL‐1β. 5‐HETE, 5‐Hydroxyeicosatetraenoic Acid; AA, Arachidonic acid; AP‐1, Activator protein‐1; CD36, Cluster of differentiation 36; COX, Cyclooxygenase; IL‐1β, Interleukin‐1β; JNK, C‐Jun N‐terminal kinase; LCFAs, Long‐chain fatty acids; LOX, Lipoxygenase; LTB4, Leukotriene B4; MSU, Monosodium urate crystals; MyD88, Myeloid differentiation primary response 88; NF‐κB, Nuclear factor kappa B; NLRP3, NOD‐, LRR‐ and pyrin domain‐containing protein 3; PGE, Prostaglandin E; ROS, Reactive oxygen species; STAT, Signal transducer and activator of transcription; TLR, Toll‐like receptor; TNF, Tumor necrosis factor.

5. The Role of Unsaturated Fatty Acids in Gout Flare

The associations between circulating unsaturated fatty acids and gout were found to be complex, according to a population‐based cohort analysis. The study revealed that baseline levels of polyunsaturated fatty acids (PUFAs), n‐6 PUFAs, and linoleic acids (LAs) were inversely related to the incidence of gout. In contrast, baseline levels of monounsaturated fatty acids (MUFAs), n‐3 PUFAs, and docosahexaenoic acids (DHAs) showed positive associations with gout flare. Furthermore, longitudinal increases in n‐6 PUFAs and LAs were linked to a reduced risk of subsequent gout flare, while an increase in n‐3 PUFAs was associated with an elevated risk [36].

PUFAs, including omega‐3 fatty acids (n‐3 PUFAs) and omega‐6 fatty acids, play significant roles in regulating lipid metabolism and inflammatory responses [37, 38]. Monounsaturated fatty acids, which mainly include oleic acid, demonstrate anti‐inflammatory properties by inhibiting the expression of tumor necrosis factor (TNF) and interleukin‐1 (IL‐1), showing promise as a therapeutic approach. In the pathogenesis of gout, arachidonic acid (ARA), an omega‐6 polyunsaturated fatty acid, serves as a precursor to several potent pro‐inflammatory mediators, such as prostaglandins and leukotrienes. It has also been reported to contribute to MSU crystal‐induced inflammation by promoting the production of TNF‐α and IL‐1β in macrophages. Omega‐3 polyunsaturated fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), demonstrate significant anti‐inflammatory effects in models of crystal‐mediated inflammation. Mechanistically, n‐3 PUFAs suppress the activation of the NLRP3 inflammasome induced by a high‐fat diet in a type 2 diabetes model in vivo. Consequently, this inhibits the subsequent activation of caspase‐1 and the secretion of IL‐1β. These processes involve the G‐protein‐coupled receptors 120 (GPR120) and 40 (GPR40), as well as their downstream scaffold protein β‐arrestin‐2 [39, 40].

6. SCFAs Process Anti‐Inflammatory Mediators in Gout Flare

Acetate, a major SCFA, has previously been shown to alleviate MSU‐induced arthritis, reduce neutrophil infiltration, and mitigate inflammatory hyperalgesia. Butyrate, another type of SCFA, has been reported to decrease palmitic acid levels and suppress the inflammatory response induced by MSU [41]. In a gout mouse model, SCFAs have been found to facilitate the resolution of neutrophilic inflammation by inhibiting NF‐κB activity and promoting the production of anti‐inflammatory mediators including IL‐10, TGF‐β, and annexin A1. This effect was also observed in mice fed a high‐fiber diet, which enhances SCFA production [42]. Furthermore, SCFAs can inhibit the production of nitric oxide and proinflammatory cytokines, including tumor necrosis factor (TNF) and cytokine‐induced neutrophil chemoattractant‐2 (CINC‐2), by neutrophils. Notably, microbiota depletion in MSU‐induced mice leads to reduced SCFA production, which correlates with decreased neutrophil infiltration, hyperalgesia, and production of IL‐1β and CXCL1. Moreover, treatment of germ‐free mice with propionate and butyrate inhibited both in vitro and ex vivo production of proinflammatory cytokines (TNF‐α and CINC‐2αβ) and NO, indicating that SCFAs have anti‐inflammatory effects by inhibiting HDAC activity and NF‐κB activation [43].

7. Role of Free Fatty Acid Receptors (FFARs) in SCFA‐Mediated Anti‐Inflammation

FFARs comprise a subfamily of G protein‐coupled receptors (GPCRs) that are activated by FFAs and their metabolites. To the present date, four FFARs (FFAR1‐4) have been identified, with FFAR2 (GPR43) and FFAR3 (GPR41) receiving particular attention for their roles in inflammatory disease pathogenesis due to their specific activation by SCFAs [44]. It has been reported that FFAR2 signaling inhibits NF‐κB nuclear translocation, consequently reducing the expression of inflammatory cytokines such as IL‐1β and IL‐6 [12, 41]. In gout patients, FFAR2 expression exhibits dynamic regulation across disease states, showing significant upregulation compared to individuals with hyperuricemia. This upregulation is particularly pronounced in the presence of MSU crystal deposition and during intercritical gout periods. Strikingly, FFAR2 expression reaches peak levels during gout flare [45].

Functional studies in GPR43‐deficient (FFAR2−/−) mice have revealed critical insights into SCFA‐mediated inflammatory responses. These animals demonstrate attenuated neutrophil recruitment following MSU crystal challenge, accompanied by reduced IL‐1β production and diminished ROS generation. These findings suggest that while SCFAs can promote inflammasome assembly and IL‐1β production, this process is partially dependent on FFAR2 signaling (Figure 2) [46].

FIGURE 2.

Proposed anti‐inflammatory mechanism of FFA in gout. SCFAs and n‐3 PUFAs exhibit anti‐inflammatory effects in the context of gout. (1) SCFAs bind to FFAR2/3, thereby inhibiting the nuclear translocation of NF‐κB, which leads to a reduction in the expression of pro‐inflammatory cytokines such as IL‐1β and enhances the production of anti‐inflammatory mediators, including IL‐10 and TGF‐β. Additionally, SCFAs suppress nitric oxide production, further decreasing the expression of pro‐inflammatory cytokines. (2) n‐3 PUFAs interact with the downstream scaffold protein β‐arrestin‐2, thereby inhibiting the activation of the NLRP3 inflammasome. This results in the suppression of caspase‐1 activation and IL‐1β secretion, processes that are mediated through GPR120 and 40. FFAR, Free fatty acid receptor; GPR, G‐protein‐coupled receptors; IL‐10, Interleukin‐10; IL‐1β, Interleukin‐1β; n‐3 PUFAs, Omega‐3 fatty acids; NF‐κB, Nuclear factor kappa B; NO, Nitric oxide; ROS, Reactive oxygen species; SCFAs, Short‐chain fatty acids; TGF‐β, Transforming growth factor‐β; TNF, Tumor necrosis factor.

8. FFAs In Gout Comorbidities

8.1. Insulin Resistance

Gout is closely associated with insulin resistance syndrome. Previous studies suggest that uric acid generation and fat accumulation were associated with fructose metabolism. Excessive fructose intake has been implicated in the development of hyperuricemia. Fructose is primarily metabolized in the liver and phosphorylated by fructokinase C, leading to a reduction in ATP levels and intracellular phosphates. The decrease in intracellular phosphate activates adenosine monophosphate (AMP) deaminase, an enzyme that converts AMP to inosine monophosphate (IMP), resulting in purine nucleotide turnover and subsequent uric acid formation [47].

The metabolic pathway begins with fructose phosphorylation to fructose‐1‐phosphate, which is then cleaved by aldolase B (ALDOB) into dihydroxyacetone phosphate (DHAP) and D‐glyceraldehyde. These intermediates subsequently enter glycolytic and gluconeogenic pathways, contributing to the synthesis of glucose, glycogen, and triglycerides [48]. This metabolic flux promotes the progression of metabolic diseases (such as glucose intolerance, dyslipidemias, and insulin resistance).

Insulin resistance is defined by impaired cellular responses to insulin's metabolic actions, while its mitogenic effects remain relatively preserved. This metabolic dysfunction leads to dysregulated lipid metabolism, characterized by increased free fatty acid release from adipose tissue and exacerbation of systemic inflammation [49, 50]. SFAs play a pivotal role in insulin resistance development through their interaction with pattern recognition receptors. Specifically, SFAs bind to TLR‐2 and 4, which are expressed on both adipocytes and macrophages. These receptors, classically involved in pathogen recognition and innate immunity, initiate pro‐inflammatory signaling cascades upon SFA engagement.

The TLR4‐SFA interaction triggers the activation of JNK, which subsequently phosphorylates insulin receptor substrate 1 (IRS‐1) at serine residues. This post‐translational modification disrupts normal IRS‐1 tyrosine phosphorylation, impairing downstream insulin signaling through the PI3K‐Akt pathway [51, 52]. Concurrently, TLR4 activation stimulates the NF‐κB signaling cascade, leading to increased transcription of pro‐inflammatory cytokines, including TNF‐α and IL‐6. These cytokines form a positive feedback loop: They further activate JNK signaling, exacerbate IRS‐1 impairment, amplify macrophage inflammatory responses, and contribute to the chronic inflammatory state characteristic of insulin resistance [52].

The inflammatory milieu created by TNF‐α and IL‐6 has particular relevance in gouty flares. These cytokines enhance macrophage activation and pro‐inflammatory polarization, increase synovial inflammation and joint destruction, and potentiate the inflammatory response to MSU crystals [26, 33]. This interplay between metabolic dysfunction and chronic inflammation highlights the bidirectional relationship between insulin resistance and inflammatory diseases, where each condition exacerbates the other through shared molecular pathways [53, 54].

Recent evidence further supports this mechanistic link. McCormick et al. reported that hyperinsulinemia leads to hyperuricemia, while the reverse causality is not observed [55]. In a study combining biochemistry with population genetics, urate transporter 1 (URAT1) has been found to be regulated by hyperinsulinemia via AKT, which phosphorylates URAT1‐Thr408 to reduce URAT1 cell‐surface abundance and urate transport activity [56]. These findings suggest that interventions targeting insulin resistance may effectively lower serum urate acid (SUA) levels and mitigate gout risk, whereas reducing SUA levels is unlikely to alleviate insulin resistance or its cardiovascular‐metabolic consequences.

8.2. Renal Fibrosis in Gouty Nephropathy

Tubular injury, characterized by apoptosis and necrosis of renal tubular epithelial cells (TECs), is a hallmark of gouty nephropathy. This injury triggers a cascade of pathological events, including interstitial inflammation and fibrosis; the underlying mechanism involves the activation of the NLRP3 inflammasome and disturbances in lipid metabolism [57].

FFAs, particularly palmitic acid, activate TECs through lipid overload, inducing mitochondrial reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress. These stressors promote NLRP3 inflammasome oligomerization, facilitating caspase‐1 cleavage and subsequent maturation of pro‐inflammatory cytokines IL‐1β and IL‐18 [58, 59]. Elevated IL‐1β levels recruit macrophages via chemokine (C‐C motif) ligand 2 (CCL2) secretion, perpetuating a pro‐inflammatory microenvironment. Chronic inflammation further stimulates fibroblast activation, marked by α‐smooth muscle actin (α‐SMA) upregulation and extracellular matrix (ECM) deposition (e.g., collagen I/III), driving tubulointerstitial fibrosis [60, 61].

8.3. Non‐Alcoholic Fatty Liver Disease

Recent research findings have underscored a critical role for elevated serum uric acid levels in the pathogenesis of metabolic disorders, including metabolic dysfunction‐associated steatotic liver disease (MASLD). Recent investigations have revealed that hyperuricemia not only promotes adipogenesis and accelerates obesity onset but also directly exacerbates hepatic steatosis through interorgan crosstalk.

Elevated SUA levels can augment lipogenesis and fat accumulation, thereby driving the development of NAFLD. Su M et al. reported that a high level of UA could induce hypertrophy of adipocytes, inhibit their hyperplasia effects potentially attributed to dysregulated leptin signaling, a hormone critically involved in fatty acid metabolism and energy homeostasis. Transcriptomic analysis further linked this phenotype to modulation of the AMPK signaling pathway, a key regulator of lipid metabolism [62]. It was also reported that uric acid influenced adipogenesis in MSC‐derived adipocytes by upregulating adipogenesis markers C/EBPα, PPARγ, and Mest while downregulating small lipid droplet formation and Wnt10b expression, a Wnt signaling molecule that inhibits adipogenesis [63]. These findings collectively highlight UA's dual role in promoting adipocyte maturation and impairing adipose tissue plasticity.

Beyond adipose remodeling, UA induces adipocyte dysfunction through oxidative stress. UA activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [64], resulting in an elevation in O2− production and subsequent ROS accumulation. Excess ROS promotes monocyte chemotactic protein‐1 (MCP‐1) production, a proinflammatory adipokine recruiting macrophages to adipose tissue, fostering a chronic low‐grade inflammatory state—a hallmark of obese adipocytes [65, 66]. This inflammatory milieu further exacerbates adipose dysfunction and systemic insulin resistance.

Furthermore, UA‐induced oxidative stress activation is potentiated by augmentation of xanthine oxidoreductase (XOR), the rate‐limiting enzyme in UA biosynthesis. XOR catalyzes the oxidation of hypoxanthine and xanthine to UA, and its activity is tightly linked to NADPH oxidase‐mediated ROS production [67]. Genetic studies in murine models demonstrate that downregulation of XOR expression exacerbates adipocyte lipid accumulation and oxidative stress, ultimately leading to age‐related obesity accompanied by insulin resistance [68]. Meanwhile, adipose tissue itself serves as a significant source of UA production through XOR activity, with this process being potently upregulated in obesity—a key driver of NAFLD development [69].

In the liver, UA disrupts metabolic homeostasis through multiple interrelated mechanisms. First, UA induces hepatic mitochondrial dysfunction, characterized by impaired oxidative phosphorylation, reduced adenosine triphosphate (ATP) production, and mitochondrial DNA damage. These structural and functional abnormalities in mitochondria exacerbate ROS generation, as evidenced by elevated levels of superoxide anions (O₂ ⁻) and hydrogen peroxide (H₂O₂) [70]. The resulting oxidative stress activates the pro‐inflammatory JNK/AP‐1 pathway. JNK/AP‐1 hyperactivation, in turn, upregulates transcription of pro‐lipogenic genes (e.g., sterol regulatory element‐binding protein 1c [SREBP‐1c], fatty acid synthase [FASN]) while suppressing genes involved in fatty acid oxidation (e.g., peroxisome proliferator‐activated receptor γ coactivator 1α [PGC‐1α]), culminating in dysregulated hepatic lipid accumulation‐manifested as steatosis, triglyceride (TG) deposition, and lobular inflammation [70]. Moreover, it modulates the expression of enzymes involved in fatty acid synthesis pathways or chemokines within the liver, disrupting lipid homeostasis [71].

9. Therapeutic Implications

Treating gout involves two key approaches: One focused on lowering uric acid levels and the other on reducing inflammation. Nonsteroidal anti‐inflammatory drugs (NSAIDs), colchicine, and glucocorticoids are commonly used and effectively alleviate pain and inflammation during acute attacks. Allopurinol, febuxostat, and benzbromarone are medications designed to lower uric acid levels [2]. However, abnormal lipid profile distribution in the body can partially contribute to the pathogenesis of gout and the development of its associated complications. Therapeutic strategies targeting FFAs indicate that this approach represents a promising novel supplementary therapeutic option.

9.1. Lipid‐Targeted Strategies Are an Important Supplementary Treatment for the Long‐Term Management of Gout

A post hoc analysis of the randomized, controlled Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial demonstrated that fenofibrate, a peroxisome proliferator‐activated receptor‐α (PPAR‐α) agonist lipid‐lowering agent, decreased serum uric acid concentrations by 20% and nearly halved the incidence of first on‐study gout events over a 5‐year treatment period [72]. Several studies also provided strong evidence that fenofibrate intervention exerted a significant reduction in serum uric acid and decreased the uric acid level by approximately 0.73 mg/dL compared to placebo [73, 74]. Notably, fenofibrate's urate‐lowering action synergizes with its lipid‐modulating properties, as evidenced by concurrent reductions in triglycerides (−35%) and LDL cholesterol (−18%) [75]. Therefore, the administration of a lipid‐lowering agent in patients with gout who also present with hyperlipidemia or obesity may contribute to the effective long‐term management of the disease.

9.2. Microbiome Modulation Serves as a Promising Supplementary Treatment Approach

Dietary fiber metabolism by gut microbiota generates bioactive SCFAs (acetate, propionate, butyrate), which exert pleiotropic effects on uric acid homeostasis. Acetate‐derived butyrate enhances intestinal barrier integrity via upregulation of tight junction proteins (e.g., occludin, ZO‐1), reducing systemic endotoxin leakage and subsequent NLRP3 inflammasome activation [75, 76]. It could ameliorate hepatic triglyceride accumulation in fructose‐insulin‐resistant rats to suppress uric acid and lactate production. An in vivo animal study demonstrates that oral administration of the Lactobacillus strain MJM60390 significantly reduces blood uric acid levels. Furthermore, supplementation with this strain in hyperuricemic model mice increases the relative abundance of the Rikenellaceae family, a known producer of the short‐chain fatty acid butyrate [77]. This contributes to the maintenance of optimal intestinal health and may serve as a potential preventive strategy against hyperuricemia. Enterobacter faecalis W5 ameliorates HUA by restoring the impaired intestinal barrier, enhancing intestinal UA secretion through the regulation of ABCG2 expression, and decreasing intestinal UA synthesis via modulation of purine metabolism [78]. These findings may provide a promising basis for the development of novel therapeutic strategies targeting HUA via intestinal intervention.

9.3. Recommendations for Diet

The dietary consumption of fish rich in omega‐3 polyunsaturated fatty acids (n‐3 PUFA) was associated with a reduced risk of recurrent gout attacks after adjusting for total purine intake [79]. A cohort study on dietary polyunsaturated fatty acids and risk of gout revealed that the intake of PUFAs is significantly and negatively associated with the risk of gout incidence, whereas arachidonic acid intake demonstrates a positive correlation with gout risk. Among the various types of PUFAs, plant‐derived ones, including alpha‐linolenic acid and linoleic acid, exhibit the strongest protective effects and are inversely related to the risk of elevated uric acid levels. In contrast, marine‐derived n‐3 PUFAs did not demonstrate a statistically significant protective association against gout [37].

Therefore, dietary recommendations for individuals with gout suggest increasing the intake of fish that are rich in n‐3 PUFAs, incorporating more alpha‐linolenic acid‐rich foods such as flaxseeds, walnuts, and rapeseed oil, and moderately increasing consumption of linoleic acid sources such as sunflower seeds, corn oil, and soybean oil. Fatty fish, which contain a higher ratio of n‐3 to n‐6 fatty acids, are also encouraged in the diet. However, clinical trials involving self‐directed supplementation with n‐3 PUFAs have produced inconsistent outcomes, and meta‐analyses have not demonstrated a significant reduction in serum uric acid (UA) levels [79, 80]. Further clinical studies are needed to evaluate the efficacy of n‐3 PUFAs from specific sources and at sufficient dosages in preventing gout flares. In clinical practice, recommendations regarding n‐3 PUFA supplementation should be made with caution.

10. Conclusion

This review establishes FFAs as molecular bridges between metabolic dysfunction and inflammatory arthritis in gout. FFAs act as metabolic‐immune rheostats in gout, with LCFAs driving inflammasome‐mediated pathology and SCFAs resolving inflammation via the microbiota‐gut axis. Future research should explore tissue‐specific FFA metabolism, temporal lipidomic changes during flares, and microbiome‐derived lipid mediators.

Author Contributions

N.L. performed the conceptualization and wrote the original draft; C.S. performed the review, editing, and supervision.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.