Targeting amino acid metabolic pathways: a novel therapeutic strategy for hyperuricemia-associated complications

Abstract

Hyperuricemia (HUA) is a metabolic disorder that contributes to the pathogenesis of gout arthritis (GA), chronic kidney disease (CKD), and cardiovascular disease (CVD). While current urate-lowering therapies effectively reduce serum uric acid levels, they fail to address the underlying metabolic dysregulation driving HUA progression and associated tissue damage. Emerging evidence highlights that dysregulated amino acid (AA) metabolism in bone, kidney, and vascular tissues plays a pivotal role in HUA-related complications. This review synthesizes recent advances in understanding AA metabolic pathways involved in HUA complications and elucidates the therapeutic potential of targeting tissue-specific AA metabolism. We propose precision modulation of AA metabolism as a promising strategy for both preventing and treating HUA-associated complications.

Introduction

Hyperuricemia (HUA) is a metabolic disease caused by disturbances in purine metabolism (Bian et al. 2025; Zhang et al. 2025), which clinically causes a wide range of complications such as Gouty arthritis (GA), Chronic kidney disease (CKD) and Cardiovascular disease (CVD) (Chang et al. 2025; Choi and Curhan 2007; Doria and Krolewski 2011; Zhao et al. 2025). In recent years, the prevalence of HUA-related complications as well as the risk of death has been increasing (Aryan et al. 2020; Wen et al. 2020), with approximately > 10% of the global population suffering from complications related to HUA (Hong et al. 2025; Zhou et al. 2024), adding to the public health burden. However, existing therapeutic strategies, including inhibition of Xanthine oxidase (XOD) activity and promoting Uric acid (UA) excretion - can reduce UA levels but have very limited therapeutic effects on the metabolic disorders and tissue damage caused by HUA (Mao et al. 2025; Wu et al. 2021a, b; Yang et al. 2024). This phenomenon suggests that intervention in UA homeostasis alone is not sufficient to combat HUA complications, and that modulation of the broader metabolic network is key to treating HUA-related complications. For example, regulating purine metabolism homeostasis and improving lipid metabolism can reduce oxidative stress and inflammation and thus improve GA (Tian et al. 2022; Yang et al. 2024; Yuan et al. 2020); glutamine supplementation and promotion of fatty acid metabolism can inhibit apoptosis and reduce renal fibrosis and renal tubular cell injury in CKD mice (Wang et al. 2023a, b; Zuo et al. 2024); and intake of proline and promotion of fatty acid oxidation can inhibit myocardial infarction and cell apoptosis in CVD mice (Shao et al. 2020; J. Wang et al. 2020a, b). Among them, Amino acid (AA) metabolism, as an upstream reaction of purine metabolism, is not only one of the causes of elevated UA, but also a central etiologic factor in the development of complications related to HUA (H. Li et al. 2022a, b, c; Nitz et al. 2022; Tran et al. 2024; Q. Wang et al. 2024a, b, c).

Elevated serum uric acid mainly damages tissues such as kidneys, blood vessels, bones and joints, in which AA metabolism plays an important role in the damage process. Studies have shown that AA metabolism can be deeply involved in the progression of HUA and its complications through the regulation of purine metabolism, oxidative stress and inflammation, and cross-organ interactions. For example, excessive metabolism of purine synthesis precursors such as glycine and glutamine triggers abnormally high Serum Uric acid (SUA)levels (Tran et al. 2024); decreased arginine metabolism leads to oxidative stress and inflammation (Brandt et al. 2022; Dai et al. 2020); furthermore, increased leucine and glutamine metabolism amplifies the inflammatory cascade of GA (Chen et al. 2024a, b; Tan et al. 2024; Yoshimura and Nomura 2022); disturbances in the metabolism of branched-chain amino acids (BCAAs) exacerbate renal fibrosis and kidney injury in CKD (Deng et al. 2025; Miao et al. 2022); and the gut microbiota -mediated metabolite of aromatic amino acids (AAA), indole sulphate (IS), disrupts bone homeostasis and has renal and cardiovascular toxicity (Billing et al. 2024; Shyu et al. 2021; Xue et al. 2022), and affects UA homeostasis through the gut-liver-kidney metabolic axis (Vanholder et al. 2022). Therefore, the regulation of AA metabolism disorders is an important strategy to combat HUA and its complications. This paper systematically reviews the key role of AA metabolism in HUA complications and its potential therapeutic strategies, and provides a theoretical basis for the development of safe, reliable, efficacious and precise drugs and methods to combat HUA complications.

Pathophysiological roles of key amino acids and their metabolites in complications of hyperuricemia

Amino acid metabolism not only provides the foundation for life processes, and its homeostasis imbalance is also closely associated with the onset and progression of HUA and its various complications. Amino acids (AAs) and their metabolites have been demonstrated to regulate serum uric acid (SUA) levels and influence the deposition of sodium urate (MSU) crystals. This influence is observed from the perspectives of UA production and excretion. Furthermore, acids (AAs) and their metabolites serve as predictive biomarkers of risk for HUA complications. The results of serum metabolome results from patients with GA indicate a significant decrease in the levels of β-alanine (Chen et al. 2025b); Patients diagnosed with clinical CKD and hyperuricemic nephropathy (HN) models frequently demonstrate elevated levels of the tryptophan metabolite, indoleacetic acid (IS) (Amatjan et al. 2023; Vial et al. 2022); A substantial increase in arginase activity was identified in the combined HUA and CVD animal model, resulting in a notable decrease in systemic arginine levels (El-Bassossy et al. 2013; Heuser et al. 2025)。It is evident that these abnormalities frequently contribute to the damage processes of tissues such as bone, kidney, and blood vessels by regulating oxidative stress, inflammatory responses, and key signalling pathways. The following sections will focus on several amino acids and their metabolic mechanisms that play crucial roles in HUA and its associated complications (As shown in Fig. 1.).

Fig. 1.

Several amino acids and their metabolic mechanisms that play crucial roles in HUA and its associated complications. Abbreviations: AA: Amino acid; HUA: Hyperuricemia; IS: Indole sulphate; NLRP3: Nucleotide- binding oligomerization domain, leucine- rich repeat and pyrin domain- containing 3; Nrf2: Nuclear factor erythroid-related factor 2; AHR: Aromatic hydrocarbon receptor; mTOR: mammalian target of rapamycin; BCAA: Branched-chain amino acids; BCKA: Branched-chain ketone acid; Hcy: Homocysteine; NO: Nitric oxide; AI: Anti-inflammatory agent

Glutamine plays a pivotal role in the maintenance of cellular energy metabolism and antioxidant balance. Its catabolic disorders have been shown to lead to impaired cellular energy metabolism (Yoo et al. 2020), enhanced autophagy and apoptosis in cells (Hou et al. 2024), and the promotion of the progression of HUA complications. MSU deposits in blood vessels have been shown to cause vascular endothelial cell damage and disrupt glutamine metabolism, resulting in reduced levels of its metabolic product, glutathione (GSH, an antioxidant) (Lana et al. 2024).This has been demonstrated to diminish the body’s antioxidant capacity, further exacerbating oxidative stress and inflammatory responses (Zhou et al. 2022).

Abnormal tryptophan metabolism has been demonstrated to be closely associated with complications of HUA. Clinical studies have indicated that isocysteine (IS), a tryptophan metabolite, accumulates significantly in patients with chronic kidney disease (CKD) (Vial et al. 2022), and contributes to the progression of renal pathology. Furthermore, disrupted tryptophan metabolism has been shown to compromise the intestinal immune barrier and exacerbate systemic inflammation. It may contribute to the development of gout (Q. Wang et al. 2024a, b, c), CKD(H. Li et al. 2022a, b, c), and CVD(Nitz et al. 2022) by regulating inflammation and oxidative stress.

Branched-chain amino acids (BCAAs), notably leucine, demonstrate substantial metabolic alterations under conditions of HUA. A study of plasma samples from human subjects revealed a positive correlation between leucine levels and CKD progression (Ishii et al. 2024), Elevated leucine levels have been shown to significantly activate the mTORC1 signalling pathway (DiMartino et al. 2025), inducing sustained activation of autophagy in the renal proximal tubules (J. Yang et al. 2025a, b), thereby causing renal injury. Additionally, MSU deposition in the kidneys has been demonstrated to inhibit BCAA metabolism, resulting in abnormally elevated BCAA levels in the kidneys. This, in turn, has been shown to activate the mammalian target of rapamycin (mTOR) pathway, further exacerbating inflammatory responses and renal fibrosis (Deng et al. 2025; J. Li et al. 2024a, b, c, d).

Furthermore, the metabolism of other amino acids, such as methionine, has also been demonstrated to interact with HUA. For instance, elevated levels of homocysteine (Hcy), an intermediate metabolite of methionine (X. Li et al. 2024a, b, c, d), have been shown to reduce antioxidant activity and increase inflammatory factor levels, thereby promoting the progression of cardiovascular disease (CVD) (Prauchner et al. 2024; Witucki and Jakubowski 2024). In addition, purine metabolism disorders have been observed to trigger gout attacks (Bian et al. 2024; Wu et al. 2023). To summary, metabolic abnormalities in multiple amino acids have been demonstrated to be closely associated with the onset and progression of HUA complications. By influencing key pathological processes such as oxidative stress, autophagy, and apoptosis, these abnormalities have been shown to profoundly contribute to the mechanisms of bone, renal, and vascular damage in HUA. Further elucidating the metabolic pathways and regulatory networks of these amino acids in specific tissues will provide a theoretical basis for the prevention and treatment of HUA complications.

Tissue-specific AA metabolism in physiopathological conditions

In the context of hyperuricemia, systemic oxidative stress and chronic inflammation underpin the pathophysiology across skeletal, renal, and vascular tissues. A central shared mechanism is the activation of the NLRP3 inflammasome, primarily triggered by the deposition of monosodium urate (MSU) crystals, which leads to the release of IL-1β and amplifies downstream inflammatory cascades(Qiao et al. 2020). Concurrently, soluble uric acid activates NADPH oxidase(Nie et al. 2021), resulting in glutathione (GSH) depletion and increased generation of reactive oxygen species (ROS)(Kwong and Wang 2020). This oxidative burden further exacerbates mitochondrial dysfunction and perpetuates pro-inflammatory signaling. These pathways closely interface with amino acid metabolism. Glutamine, for instance, serves as a precursor for GSH synthesis, thereby counteracting oxidative stress, while its metabolite α-ketoglutarate can suppress NLRP3 inflammasome activation(Lana et al. 2024). Arginine metabolism supports vascular nitric oxide production and, via arginase-1 in macrophages, drives the synthesis of anti-inflammatory polyamines(Shosha et al. 2023). Conversely, dysregulation of branched-chain amino acids (BCAAs) and tryptophan metabolites aggravates oxidative stress and fibrotic processes through mechanisms such as mTOR hyperactivation and aryl hydrocarbon receptor (AHR) signaling(Deng et al. 2025; J. Li et al. 2024a, b, c, d). Targeting these interconnected pathways—NLRP3 activation, oxidative stress, and metabolic reprogramming—holds promise for developing multi-organ therapeutic strategies to alleviate hyperuricemia-associated complications, including bone erosion, renal fibrosis, and cardiovascular disease.

Bone tissue

Bone tissue homeostasis is maintained through a dynamic equilibrium between osteoblast-mediated formation and osteoclast-mediated resorption. Under normal physiological conditions, osteoblasts import free amino acids from the bloodstream via specific transporters such as SLC1A5 and SLC38A2 to support cellular function and anabolic activity (Sharma et al., 2021; Shen et al. 2022). Conversely, osteoclasts release amino acids through bone resorption, facilitating skeletal remodeling (H. Wang et al. 2023a, b). The balance of amino acid metabolism is thus a critical determinant of bone tissue homeostasis. Experimental evidence indicates that reduced availability of glutamine (Gln) or proline (Pro) suppresses the synthesis of RUNX2, a key transcription factor governing osteoblast differentiation and bone formation (Hu et al. 2023), thereby impairing osteoblast maturation. In contrast, adequate Gln or Pro intake upregulates RUNX2 expression and promotes osteogenic differentiation (Sharma et al., 2021; Shen et al. 2022). Meanwhile, mature osteoclasts rely primarily on glycolysis for energy (Li et al. 2020). Inhibition of glycolysis significantly suppresses osteoclast differentiation (Kachler et al. 2024), highlighting the metabolic dependency of osteoclastic activity. As shown in Fig. 2, in patients with GA, high levels of SUA cause MSU crystals to be deposited in the joints and periarticular tissues (Weaver et al. 2021), which then triggers an inflammatory state by inducing macrophage polarization and activation of inflammatory vesicles, such as NLRP3 (Wang et al. 2024a, b, c; G. Wu et al. 2021a, b). Osteoclasts are stimulated by the pro-inflammatory factor TNF-α (Kitaura et al. 2020), which promotes glycolysis and inhibits oxidative phosphorylation, and osteoclasts are accelerated to differentiate (Doi et al. 2022; Kachler et al. 2024), leading to increased bone resorption and destruction of the bone structure. In addition to the above mechanisms, MSU crystals induce oxidative stress as well as mitochondrial dysfunction, which further amplifies pro-inflammatory signaling through ROS-dependent pathways (Yin et al. 2020). Whereas modulation of AA metabolism can reverse the above situation, Arg can inhibit inflammation-induced osteoclastogenesis by restoring oxidative phosphorylation of osteoblasts and thereby inhibiting osteoclastogenesis (Cao et al. 2024), and also promotes the synthesis of anti-inflammatory polyamines via Arginase-1 (Arg-1) in M2 macrophages (Shosha et al. 2023); Trp is catabolized in dendritic cells by indoleamine 2,3-dioxygenase (IOD) to produce kynurenine that inhibits T-cell proliferation and promotes regulatory T-cell (Treg) differentiation of kynurenine (Qu et al. 2023; Stone and Williams 2023), which attenuates the inflammatory response. In addition, studies have shown that joint pain, cartilage wear and tear are strongly associated with collagen deficiency (Feng et al. 2024). Under normal physiological conditions, chondrocytes take up Gly, Pro and hydroxyproline to synthesize collagen, but when the content of Pro and hydroxyproline decreases, the raw materials for collagen synthesis are reduced (Bai et al. 2023), and chondrocytes are unable to synthesize collagen, which affects the self-repairing ability of the damaged cartilage (Gao et al. 2024), leading to joint pain and increased wear and tear of cartilage, and contributing to the progression of GA. (See Table 1 for details.)

Fig. 2.

HUA-induced bone tissue injury and key amino acid metabolism. AA metabolism can improve GA by inhibiting oxidative stress as well as inflammatory responses, promoting osteoblast maturation, inhibiting osteoclast differentiation to maintain bone homeostasis, and promoting cartilage self-repair by promoting collagen synthesis by chondrocytes. Abbreviations: AA: Amino acids; UA: Uric acid; MSU: Monosodium urate; GA: Gout arthritis; OXPHOS: Oxidative phosphorylation; AI: Anti-inflammatory agent; NLRP3: Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3; NETs: Neutrophil extracellular traps; ROS: Reactive oxygen species; TNF-α: Tumour necrosis factor-alpha; IL-1β: Interleukin-1 beta

Table 1.

AA metabolic modulation targeting intervention in HUA-induced GA. Abbreviations: GLS1: glutaminase 1; α-KG: α-ketoglutarate; NAC: N-acetylcysteine; GSH: Glutathione; ROS: reactive oxygen species; CBS: cystathionine beta-synthase; TRPV1: transient receptor potential vanilloid subfamily 1; ATG5: autophagy related protein 5; Sesn2: Sestrins2; IOD: indoleamine 2,3-dioxygenase

Pathological mechanism	Coregulated AAs	Regulatory mechanisms and intervention effects	Quote
Activation of NLRP3 inflammatory vesicles	Gln	Inhibition of macrophage GLS1→Reduction of α-KG/ HIF-1α→Reduced IL-1β maturation	(Chen et al. 2025a; Tannahill et al. 2013)
		Exogenous Gln deprivation→ Blocking NLRP3 oligomerization
NETosis mediates joint damage	Cys	Supplementation with NAC→ Increase GSH levels→ Inhibit ROS/PAD4→Reducing NETs formation	(Byun et al. 2024; Safi et al. 2018)
		Activation of CBS→ Increased H2S generation→ Inhibition of TNF-α/IL-8 cascade response	(Li et al. 2013; Mishra et al. 2020)
Synoviocyte mTORC1 hyperactivation	Leu	Limit Leu intake→ Inhibits mTORC1-S6K signaling→ Reduces synovial fibroblast proliferation	(Karonitsch et al. 2018; Ma et al. 2021)
Painful nerve sensitization	Trp	Inhibits 5-HT production→ Blocking TRPV1 activation→ Compassion↓	(Fischer et al. 2017)
Cartilaginous matrix injury (CMI)	Pro	Supplementary Pro→ Collagen synthesis materials↑→Cartilage self-repair↑	(Bai et al. 2023; Gao et al. 2024)
	Trp	Inhibition of Trp indole metabolic pathway→ IS level↓→ ATG5 expression↓→Autophagy in damaged chondrocytes↑→Cartilage matrix repair↑	(Qiang et al. 2021; Zhang et al. 2021)
Osteoclastogenesis	Leu	Intake of Leu→ Activation of the Sesn2/AMPK signaling pathway→ Inhibits osteoclastogenesis	(Kim et al. 2024; Wolfson et al. 2016)
Inflammation subsides	Arg	Activation of Arg-1→Anti-inflammatory polyamines↑	(Shosha et al. 2023)
	Trp	IOD↑→Kynurenine↑→T-cell proliferation↓→Inflammation response↓	(Siska et al. 2021; Stone and Williams 2023)

Renal

The renal plays an important role in the metabolism and reabsorption of AA, and likewise, AA metabolic homeostasis plays an important role in maintaining normal physiological function of the renal. Under normal physiological conditions, glutaminase in the proximal tubules of the renal metabolizes Gln for energy and also synergizes protein reabsorption of most AAs via sodium ions to maintain normal physiological activity (Lewis et al. 2021; Navarro Garrido et al. 2022). As shown in Fig. 3, in patients with HUA, soluble UA as well as MSU crystals deposited in renal tissues are capable of causing renal injury through a variety of mechanisms. Soluble UA causes oxidative stress in the renal by activating NADPH oxidase, depleting antioxidants such as glutathione (GSH) and inducing cellular mitochondrial dysfunction, leading to apoptosis as well as renal fibrosis (Kwong and Wang 2020; Liu et al. 2023a, b; Nie et al. 2021), and also directly induces epithelial-mesenchymal transition (EMT) in renal tubular cells thereby driving renal fibrosis (Li et al. 2025). MSU crystals deposited in the renal then exacerbate renal inflammation as well as fibrosis by activating NLRP3 inflammasome and releasing pro-inflammatory factors (Zhou et al. 2022). Studies have shown that supplementation with N-acetylcysteine (NAC), a synthetic precursor of GSH, can attenuate UA-induced oxidative stress as well as activation of NLRP3 inflammatory vesicles in the renals by increasing the level of GSH (Lana et al. 2024; Mapamba et al. 2022; Xu et al. 2024), thereby alleviating the progression of CKD as well as renal injury caused by UA. When abnormal renal function such as proximal tubular injury causes reabsorption dysfunction, the urinary excretion of AAs increases, plasma levels of EAAs decrease, and renal injury is aggravated (Rajendran et al. 2020). Renal damage is likewise exacerbated when there are abnormally elevated levels of EAAs. Studies have shown that the accumulation of BCAAs can over-activate the mTOR signaling pathway (Liu et al. 2024a, b), cause mitochondrial damage and apoptosis (Zheng et al. 2024), and promote M2 macrophage polarization and pro-fibrosis, thereby exacerbating renal fibrosis and inflammatory injury (H. Chen et al. 2024a, b; Lu et al. 2022). After targeted knockdown of Krüppel-like factor 6 (KLF6), a transcriptional repressor of BCAAs catabolism, BCAAs catabolism was enhanced, and renal fibrosis and renal injury were attenuated (Piret et al. 2021). In addition to the above mechanisms, the metabolite of the Trp indole pathway, indole sulfate (IS), has been found to promote renal fibrosis and accelerate the progression of CKD through the activation of the Aromatic hydrocarbon receptor (AHR)/Snail-family transcriptional repressor protein 1 (SNAI1) signaling pathway (Chen et al. 2023; Thome et al. 2024). When interfering with Trp metabolism and activating the tryptophan-kynurenine pathway, its metabolite kynurenine attenuates the inflammatory response in the renal by inhibiting the production of NLRP3 inflammatory vesicles (C. Wang et al. 2024a, b, c). (See Table 2 for details)

Fig. 3.

HUA-induced kidney injury and core regulation of AAs. AA metabolism ameliorates HUA-induced renal injury by inhibiting oxidative stress, reducing lipid accumulation, and suppressing renal fibrosis by inhibiting renal EMT as well as myofibroblast differentiation. In the process of AA regulation, Trp metabolites produced by intestinal microbiota also play an important role. Abbreviations: UA: Uric acid; IS: Indole sulfate; Sesn2: Sestrins2; PPAR-α: Peroxisome proliferator-activated receptors; MSU: Monosodium urate; BCAAs: Branched-chain amino acids; mTOR: Mammalian target of rapamycin; AMPK: Adenosine 5‘-monophosphate (AMP)-activated protein kinase; GPX4: Glutathione peroxidase 4; ROS: Reactive oxygen species; Mac: Macrophages; NLRP3: Nucleotide- binding oligomerization domain, leucine- rich repeat and pyrin domain- containing 3; EMT: Epithelial-mesenchymal transition; NF-κB: Nuclear Factor Kappa B; AHR: Aryl hydrocarbon receptor; SNAI1: Snail family transcriptional repressor 1; TLR4: Toll-like receptor 4; MyD88: Myeloid differentiation primary response protein 88

Table 2.

Modulation of AA metabolism reverses HUA-induced CKD. Abbreviations: EMT: Epithelial-mesenchymal transition; bcaas: Branched-chain amino acids; PHGDH: phosphoglycerol dehydrogenase; GSH: glutathione; ROS: reactive oxygen species; NF-κB: nuclear factor kappa B; TLR: Toll-like receptor; AHR: Aryl hydrocarbon receptor; SNAI1: snail family transcriptional repressor 1; Sesn2: Sestrins2; PPARs: peroxisome proliferator-activated receptors; GPX4: glutathione peroxidase 4

Pathological mechanism	Coregulated AAs	Regulatory mechanisms and intervention effects	Quote
Renal tubular EMT transformation	Trp	Supplementation of 5-HTP activates 5-HT2B receptors→ Inhibition of SMAD2 phosphorylation→ Renal EMT Transformation↓	(Wenglén et al. 2023)
	BCAAs	Promote catabolism of BCAAs→ mTOR signaling↓→Activation of pro-inflammatory macrophages↓→Renal EMT Transformation↓	(Deng et al. 2025)
Mitochondrial dysfunction	Ser	Activation of PHGDH→ Increases serine synthesis→ Promotes GSH regeneration→ Reduction of renal cell ROS	(Amelio et al. 2014)
Renal fibrosis	Gly	Inhibition of NF-κB activation→ Reducing renal fibrosis	(Hasegawa et al. 2012; Tian et al. 2023)
		Gly inhibits TLR 4/myeloid differentiation marker 88 (MyD88)→Renal fibrosis↓	(L. Huang et al. 2024a, b; Xu et al. 2018)
	Trp	Inhibition of the indole metabolic pathway of Trp→ IS level↓→Inhibition of AHR/SNAI1 signaling→ Renal fibrosis↓	(Chen et al. 2023; Thome et al. 2024)
	BCAAs	Knockdown of KLF6→BCAAs catabolism↑→Pro-fibrotic↓→Renal fibrosis↓	(H. Chen et al. 2024a, b; Lu et al. 2022; Piret et al. 2021)
Renal lipid accumulation	Leu	Limiting Leu intake→ Inhibition of Sesn2/AMPK/ PPARs signaling pathway activation→ Renal lipid accumulation↓	(Dong et al. 2024; Han et al. 2021; Wolfson et al. 2016)
Iron death	Cys	Activation of Cys/Glu reverse transporter protein (System Xc−)→Intracellular Cys↑→ GPX4 activity restoration→ Iron death↓	(Alborzinia et al. 2022; F. J. Li et al. 2022a, b, c)

Blood vessel

Blood vessels, as conduits for blood transportation, bear the important responsibility of transporting AAs, which are transported with the blood to tissues throughout the body. AA transporters such as LAT1 and SNAT are present on the surface of endothelial cells that form the inner wall of blood vessels and regulate the uptake and release of AAs (Bhakuni et al. 2024; Ramsay et al. 2024). Under normal physiological conditions, vascular endothelial cells can catabolize and metabolize Arg through nitric oxide synthase (eNOS) to produce nitric oxide (NO) (N. Zhang et al. 2023a, b), which protects and maintains the normal physiological function of blood vessels (Hill et al. 2021; Teoh et al. 2020). As shown in Fig. 3, studies have shown that soluble UA inhibits NO production by inhibiting endothelial-type eNOS activity, leading to endothelial dysfunction (Choi et al. 2014), while Arg, as a precursor of NO synthesis (Hu et al. 2024), can restore the eNOS/NO/cGMP signaling axis to improve vasodilatory function (Javrushyan et al. 2022). A meta-analysis showed that oral Arg significantly reduced systolic blood pressure (SBP) and Diastolic blood pressure (DBP) and attenuated vascular damage in the test subjects (Shiraseb et al. 2022). In addition, UA accelerates atherosclerotic plaque formation by activating the renin-angiotensin system (RAS) and NADPH oxidase, inducing oxidative stress (Nie et al. 2021; Pai et al. 2022), and promoting the proliferation of vascular smooth muscle cells (VSMC) and collagen deposition (Xu et al. 2023). MSU crystals deposited in blood vessels, on the other hand, are capable of directly damaging vascular endothelial cells and activating NLRP3 inflammatory vesicles, releasing pro-inflammatory factors, such as IL-1β (Zhou et al. 2022), to promote vascular inflammation. Gln serves as a synthetic precursor of GSH, which, in addition to synthesizing GSH to counteract UA-induced oxidative stress (Lana et al. 2024), can be metabolized to α-KG to ameliorate vascular lesions, such as vascular calcification, by up-regulating the expression of the DNA demethylase 10–11 translocation 2 (TET2), as well as inhibiting NLRP3 inflammatory vesicles (Fu et al. 2025). In contrast, when Gln metabolism is abnormal in the vasculature, pathogenic activation of pulmonary arterial fibroblasts (PAAFs) is facilitated by transcriptional coactivators YAP and TAZ, and Pro and Gly metabolism as well as collagen biosynthesis are accelerated, resulting in increased perivascular collagen deposition and thus exacerbating vascular sclerosis (Rachedi et al. 2024). In addition to the above mechanisms, abnormalities in Phe and Met metabolism also affect the normal physiologic function of blood vessels. Phenylacetylglutamine (PAGln) is a metabolite of Phe (Zhu et al. 2023), and abnormally elevated levels of PAGln cause oxidative stress, leading to vascular endothelial cell activation and vascular endothelial dysfunction (Gao et al. 2024). When Met metabolism is impaired, excessive accumulation of its intermediary metabolite Hcy promotes inflammation as well as endothelial cell damage and accelerates the progression of CVD through inhibition of Nrf2 expression and impairment of antioxidant enzyme activity (Prauchner et al. 2024; Zhang et al. 2023a, b). Therefore, intervening in the metabolic processes of Phe and Met by regulating their metabolic pathways and reducing the accumulation of harmful metabolites is of great significance in combating CVD. (See Table 3 for details) (Fig. 4).

Table 3.

Modulation of AA metabolism to reverse HUA-induced CVD. Abbreviations: eNOS: endothelial nitric oxide synthase; GLS1: glutaminase 1; α-KG: -Ketoglutaric acid; NF-κB: nuclear factor kappa B; ROS: reactive oxygen species; P4HA1: proline 4-hydroxylase subunit alpha 1; PAGln: Phenylacetylglutamine; GSH: glutathione

Pathological mechanism	Coregulated AAs	Regulatory mechanisms and intervention effects	Quote
Endothelial eNOS uncoupling	Arg	Restoration of the eNOS/NO/cGMP signaling axis→Improves vasodilatory function	(Javrushyan et al. 2022)
Plaque macrophage inflammation	Gln	Suppression of GLS1→Blocking α-KG/HIF-1α→Macrophages secrete IL-1β↓	(Bai et al. 2025; Su et al. 2025)
		Enhanced glutamine synthetase (GS)→Inhibition of NF-κB activation	(Li et al. 2023)
Hcy accumulation	Met	Met limits intake→ Hcy precursor↓→Reversal of HUA-induced Hcy rise	(Zhang et al. 2023a, b)
VSMC calcification	Gln	Gln supplementation→α-KG↑→TET2 expression↑→vascular calcification↓	(Fu et al. 2025)
UA activates the RAS system	Tyr	Agonist dopamine D1 receptor→ Blocking the AT1R signal→ Inhibition of myocardial ROS production	(Asghar et al. 2007; Yang et al. 2015)
Myocardial fibrosis	Pro	Inhibition of P4HA1→Collagen deposition and myocardial fibrosis↓	(Cencioni et al. 2025; Yang et al. 2025a, b; Zhao et al. 2019)
Platelet aggregation	Phe	Phe restricted intake→ Platelet aggregation↓	(Huang et al. 2024a, b)
Oxidative stress	Phe	Limiting Phe metabolism→ PAGln level↓→Oxidative stress↓	(Gao et al. 2024)
	Gln	Gln intake→GSH synthesis↑→Oxidative stress↓	(Lana et al. 2024)

Fig. 4.

HUA-induced vascular injury and core regulatory AAs. AA metabolism may improve CVD by inhibiting HUA-induced oxidative stress as well as inflammatory responses and inhibiting abnormal migration of vascular smooth muscle cells. Abbreviations: MSU: Monosodium urate; UA: Uric acid; NADPH: Nicotinamide adenine dinucleotide phosphate; eNOS: Endothelial nitric oxide synthase;α-KG: α-Ketoglutaric acid; COL: Collagen; VSMC: Vascular smooth muscle cells; Mac: Macrophage; NLRP3: NOD-like receptor thermal protein domain associated protein 3; IL-1β: Interleukin-1 beta; ASCVD: Atherosclerotic Cardiovascular Disease

Translating AA metabolic modulation into HUA complication therapies

Because of the close relationship between AA levels and disturbed AA metabolism and HUA complications, restoration of amino acid homeostasis may provide a new strategy for mitigating HUA complications. In this sections, we summarize approaches to improve AA metabolism, including through modification of diet, medications, and intestinal flora, and discuss the role of the above approaches in ameliorating HUA complications.

Dietary modulation of amino acid homeostasis

The human body acquires AAs from both endogenous synthesis—which provides non-essential AAs—and dietary intake, which supplies essential AAs (EAAs) that cannot be produced internally. Consequently, dietary regulation is essential for maintaining AA homeostasis. Appropriate supplementation of certain AAs, such as arginine (Arg), can effectively reduce systemic inflammation. Moderate consumption of Arg-rich foods—including sesame seeds, chia seeds, and deep-sea fish—as well as Arg supplements, helps preserve mitochondrial membrane permeability and stabilizes intracellular redox homeostasis. This in turn attenuates mitochondria-mediated apoptosis (Tuell et al. 2021), thereby slowing the progression of complications associated with HUA (Tang et al. 2023; Ye et al. 2022). In addition, because patients with HUA complications are often accompanied by abnormally high levels of BCAAs, AAA, or Met, patients with HUA complications should try to substitute foods that are low in BCAAs, AAA, and Met. Liu et al. found that plant-based diets such as soy protein and safflower seed oil significantly suppressed the inflammatory response caused by HUA (Y. F. Liu et al. 2024a, b). Randomized controlled trials have shown that the choice of a plant-based low-protein diet can intervene in the progression of CKD by supplementing dietary fiber and significantly reducing the production of intestinal-derived uremic toxins, especially IS, in CKD patients (Yang et al. 2021).However, this does not mean that protein intake causes elevated UA, whereas high purine intake is the root cause of elevated UA. Studies have shown that dairy (animal protein) intake instead reduces UA levels (Silva et al. 2020), for example whey protein in milk has been shown to improve HUA by promoting UA excretion (Qi et al. 2024). In contrast, intake of foods high in purines, such as insects, significantly elevated UA levels (Sabolová et al. 2023).

Modulating AA homeostasis with natural therapeutics

Natural medicines have shown promising efficacy in the treatment of HUA complications, and their therapeutic mechanisms are closely related to the regulation of AA metabolism. Curcumin is extracted from the rhizome of Curcuma longa (Liu et al. 2023a, b). Glutathione is a tripeptide composed of Gln, Cys, and Gly. Song et al. found that curcumin modulates Phe metabolism as well as Arg-Pro metabolism to increase glutathione levels and attenuate oxidative stress using a zebrafish model exposed to ethanol (Song et al. 2022a, b). Andrographolide is extracted from pomegranate rind (Ge et al. 2022), and Li et al. found that andrographolide can improve oxidative stress by increasing glutathione peroxidase activity to promote GSH scavenging of free radicals in vivo, which has a modulating effect on multi-tissue redox imbalance caused by HUA (Ma et al. 2025). In addition, Hu et al. found that the Cimicifugae Rhizoma - Smilax glabra Roxb herb pair could attenuate inflammatory cell infiltration by improving Phe and Tyr metabolism (Hu et al. 2022). Li et al. found that Huangqin decoction could up-regulate Trp and Ala content and inhibit apoptosis by activating the mTOR pathway to improve the inflammatory response, which could attenuate the multi-tissue inflammatory response caused by HUA (Li et al. 2022a, b, c). Simiao pills, composed of four Chinese herbs, Phellodendri Chinensis Cortex, Swordlike Atracylodes Rhizome, Radix Achyranthis Bidentatae, and Coicis Semen, are widely used clinically for the treatment of HUA and its complications. By performing serum metabolomics analysis on HUA rats, Bai et al. found that Si-Miao Pills could reverse the pathological process of HUA by correcting the disordered purine metabolism as well as the tricarboxylic acid cycle (Shan et al., 2021). Fisetin is widely found in vegetables and fruits, and Qian et al. found that in a mouse model of HUA-induced CKD, fisetin attenuated HUA-induced renal injury by inhibiting the activation of AHR receptors by intestinal metabolites of Trp (Ren et al. 2021).

Gut microbiota-mediated regulation of amino acid metabolism

Disturbances in AA metabolism due to gut microbial dysbiosis are also a factor that exacerbates the progression of HUA complications. Altered gut microbiota has been found to exacerbate HUA complications in patients with HUA complications as well as in a variety of rodent models by promoting AAA catabolism and contributing to the accumulation of uremic toxins (S. Li et al. 2024a, b, c, d; Wang et al. 2020a, b). In addition, it has been shown that alterations in intestinal flora disrupt amino acid transport by damaging the intestinal barrier, resulting in lower serum AA levels and inducing disturbances in purine metabolism as well as the immune response, thus exacerbating HUA and its complications (S. Song et al. 2022a, b). All these results suggest that changes in the gut microbiota affect amino acid metabolism in HUA complications, and that targeting the gut microbiota to regulate AA metabolism has good efficacy in treating HUA complications. It has been shown that Clostridium perfringens can heterologously express Clostridium perfringens arginine deiminase (ADI) thereby enhancing Arg bioavailability and attenuating the body’s inflammatory response (Li et al. 2024a, b, c, d). By decreasing the abundance of intestinal flora associated with BCAAs synthesis, such as Fusobacterium, Streptococcus, and Sulfobacillus, it is also possible to reduce serum BCAAs levels and attenuate the inflammatory response (Bao et al. 2022). Increasing the abundance of Allobaculum and Candidatus sacchairmonas (flora associated with the maintenance of homeostasis in amino acid metabolism) in GA mice also corrects disturbed AA metabolism and repairs the intestinal barrier, ameliorating the inflammatory response (Song et al. 2023).

Discussion

As outlined in this article, the pathogenesis of complications in hyperuricemia (HUA) involves not only elevated uric acid per se, but also organ-specific reprogramming of AA metabolism. Such metabolic reprogramming directly contributes to tissue damage in bone, kidney, and vasculature associated with HUA complications. This review systematically examines HUA-induced disruptions in AA metabolism and elucidates the mechanisms through which these disturbances drive pathology across different tissues, thereby identifying potential therapeutic targets for mitigating HUA-related complications.

Disorders of AA metabolism are the common pathological basis for the development of HUA complications, and they drive tissue damage through three main mechanisms: (1) Uncontrolled upstream purine metabolism. Excessive supply of purine synthesis precursors such as Gly and Gln directly induces an increase in UA levels (Tran et al. 2024), while intestinal flora-mediated metabolism of AAA affects UA excretion by interfering with the “intestinal-hepatic-kidney” axis (S. Li et al. 2024a, b, c, d; Vanholder et al. 2022; Wang et al. 2020a, b). (2) Tissue-specific disorders of AA metabolism. In bone and renal tissues as well as in the vasculature, the different pathological mechanisms due to HUA complications correspond to different AA metabolic regulation mechanisms. In bone and joint, Gln, Cys, Arg, Trp, etc. inhibit inflammatory cascade reaction (Shosha et al. 2023; Stone and Williams 2023; Tannahill et al. 2013), Pro, Leu, Trp, etc. protect the homeostasis of bone tissues, etc. (Bai et al. 2023; Karonitsch et al. 2018; Ma et al. 2021; Qiang et al. 2021; Zhang et al. 2021); in the renal, Trp, Gly, etc. inhibit renal EMT and the process of fibrosis (Chen et al. 2023; Hasegawa et al. 2012; L. Huang et al. 2024a, b; Thome et al. 2024; Tian et al. 2023; Xu et al. 2018), Ser, Leu, etc. maintain the normal physiological function of renal cells, etc. (Amelio et al. 2014; Dong et al. 2024; Han et al. 2021; Wolfson et al. 2016); in the vascular, Arg, Gln, Pro improves the cardiovascular calcification, fibrosis, etc. (Cencioni et al. 2025; Fu et al. 2025; Javrushyan et al. 2022; Yang et al. 2025a, b; Zhao et al. 2019), Phe affects platelet aggregation, etc. (Huang et al. 2024a, b). (3) Cross-organ metabolic disturbances. Some metabolites of intestinal flora are toxic to bone tissue (Shyu et al. 2021), the renal as well as the vascular (Billing et al. 2024; Xue et al. 2022), leading to a metabolic vicious circle.

However, diverse studies have shown a bidirectional nature of the regulation of amino acid metabolism to combat the disease; on the one hand, restricting the intake of certain AAs has a therapeutic effect on HUA complications, but at the same time, appropriate intake of certain AAs is rather beneficial for the maintenance of tissue homeostasis and the protection of tissues from damage. For instance, Glutamine demonstrates a well-documented dualistic effect in HUA and its associated complications. As a pivotal nitrogen source for de novo purine synthesis, its excessive metabolism stimulates uric acid production and exacerbates tissue damage (Tran et al. 2024). However, it also functions as a vital substrate for immune regulation and the synthesis of the antioxidant glutathione, thereby attenuating inflammation and oxidative stress (Lana et al. 2024) (As shown in Fig. 5). This paradoxical role presents a central dilemma in clinical management and necessitates a shift towards precision intervention strategies based on multidimensional contextual factors:1. The disease stage dictates therapeutic priority. During the acute inflammatory phase of gout, short-term glutamine supplementation may be prioritized to leverage its anti-inflammatory and antioxidant properties for symptom relief. In contrast, for chronic hyperuricemia, the strategy should pivot towards suppressing excessive glutamine catabolism in target tissues to reduce urate production at its source. 2. Tissue-specific metabolic demands require targeted interventions. Glutamine is vital for maintaining intestinal mucosal integrity and lymphocyte function. Therefore, an ideal approach would precisely inhibit glutamine metabolism in pathologically hyperactive cells (e.g., renal tubular epithelial cells, activated synovial cells) while preserving its physiological functions in healthy tissues. 3. Comorbidities, such as chronic kidney disease or metabolic syndrome, reshape the risk-benefit profile by altering systemic glutamine homeostasis. 4. The timing and modality of intervention must be precisely matched to the clinical context. Pharmacological inhibition of glutaminase and nutritional supplementation of glutamine differ fundamentally in their mechanisms of action, onset of effects, and applicable scenarios. Clinical choices should be individualized based on the patient’s disease stage and overall metabolic status. 5. Identifying dynamic biomarkers, such as the potential of markers such as glutaminase 1 activity, glutamate/glutamine ratio, or related metabolomic features to facilitate the identification of patients with distinct metabolic phenotypes is a subject that merits further investigation. The development of these markers could assist in the formulation and adjustment of personalised treatment regimens.

Fig. 5.

The Functions and Applications of Glutamine. Glutamine demonstrates a dual and context-dependent role in the management of HUA and its complications. While enhanced glutamine metabolism can contribute to elevated UA levels, supplementation with glutamine has been shown to ameliorate oxidative stress and inflammation. This paradox underscores the need for a multidimensional and personalized strategy in its clinical application. Abbreviations: UA: Uric acids; GLS1: Glutaminase 1; Mac: Macrophages; NLRP3: Nucleotide- binding oligomerization domain, leucine- rich repeat and pyrin domain- containing 3

Although targeted modulation of AA metabolism holds promise for mitigating HUA complications, key barriers to its clinical translation remain. The off-target effects of direct intake or restriction of some AAs may instead exacerbate tissue damage, so attention should be paid to organ targeting when regulating AA metabolism, such as selecting renal-targeted glutaminase inhibitors. Direct administration or restriction of specific amino acids may induce off-target effects that exacerbate tissue damage. Therefore, interventions aimed at modulating amino acid metabolism should emphasize organ-selective targeting—for instance, through the use of kidney-specific glutaminase inhibitors. Additionally, interindividual variability in gut microbiota composition can compromise the efficacy of amino acid–based strategies for managing HUA complications. Consequently, integrating multi‑omics approaches—such as metagenomics and metabolomics—to design personalized probiotic consortia tailored to an individual’s microbial profile holds significant promise for advancing individualized therapeutic regimens.

Conclusion

This review highlights the dual role of AA metabolism in HUA complications, functioning both as a driver of pathology and a potential therapeutic target. Dysregulated AA metabolism in bone, kidney, and blood vessel promotes a vicious cycle of inflammation and oxidative stress, indicating that interventions targeting tissue‑specific metabolic pathways may offer greater efficacy. Dietary and natural medicine‑based approaches underscore the relevance of metabolic reprogramming in disease management. Furthermore, intestinal microbiota modulation—which influences AA metabolism via host‑microbial metabolic interactions—provides a rationale for precisely tuning the gut microecosystem to alleviate HUA‑related complications.

Author contributions

XZ: Investigation, Software, Visualization, Writing--original draft. WW: Investigation, Writing-original draft. LY, YS, HS, GL: Investigation, Project administration, Supervision. XZ, HS: Investigation. XW: Conceptualization, Project administration, Supervision, Funding acquisition, Writing-review & editing.

Funding

This work was supported by the National Natural Science Foundation of China (U23A20501, 82404816), the Guangdong Basic and Applied Basic Research Found Project (2023A1515110703), the key research and development plan projects of Heilongjiang Province (2022ZX02C04), the State Key Laboratory of Dampness Syndrome of Chinese Medicine (SZ2021ZZ49, SZ2022KF16), and the Guangdong Academy of Traditional Chinese Medicine “Young Talents Program” Project (SZ2024QN06).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.