Hyperuricemia and its related diseases: mechanisms and advances in therapy

Abstract

Hyperuricemia, characterized by elevated levels of serum uric acid (SUA), is linked to a spectrum of commodities such as gout, cardiovascular diseases, renal disorders, metabolic syndrome, and diabetes, etc. Significantly impairing the quality of life for those affected, the prevalence of hyperuricemia is an upward trend globally, especially in most developed countries. UA possesses a multifaceted role, such as antioxidant, pro-oxidative, pro-inflammatory, nitric oxide modulating, anti-aging, and immune effects, which are significant in both physiological and pathological contexts. The equilibrium of circulating urate levels hinges on the interplay between production and excretion, a delicate balance orchestrated by urate transporter functions across various epithelial tissues and cell types. While existing research has identified hyperuricemia involvement in numerous biological processes and signaling pathways, the precise mechanisms connecting elevated UA levels to disease etiology remain to be fully elucidated. In addition, the influence of genetic susceptibilities and environmental determinants on hyperuricemia calls for a detailed and nuanced examination. This review compiles data from global epidemiological studies and clinical practices, exploring the physiological processes and the genetic foundations of urate transporters in depth. Furthermore, we uncover the complex mechanisms by which the UA induced inflammation influences metabolic processes in individuals with hyperuricemia and the association with its relative disease, offering a foundation for innovative therapeutic approaches and advanced pharmacological strategies.

Fig. 1

The timescale and historical development of hyperuricemia (depicted in light red) and hyperuricemia treatment (depicted in dark red) from 1944 to June 2024, along with the volume of published literature, have been analyzed using data extracted from PubMed. The search criteria included “hyperuricemia*“ in conjunction with terms such as “history”, “medicine”, “treatment”, “therapy”, “drug”, “mechanism”, “genetic”, and “uric acid”

Fig. 2

Consumption of purine-rich meats such as beef, pork, lamb, and seafood like oysters, shrimp, and tuna, as well as dietary fructose, are known to elevate uric acid (UA) production. Additionally, alcohol metabolism from beer and distilled spirits, along with certain medical conditions such as tumor lysis syndrome and obesity, pose increased risks for hyperuricemia. Hepatic metabolism of uric acid involves the sequential processing of purine nucleotides, including adenosine monophosphate (AMP), guanosine monophosphate (GMP), and inosine monophosphate (IMP). IMP plays a pivotal role as a key intermediate in purine nucleotide biosynthesis, serving as a precursor for the synthesis of both adenosine monophosphate (AMP) and guanosine monophosphate (GMP). Moreover, IMP can be enzymatically deaminated by IMP dehydrogenase, leading to the formation of inosine. Inosine, in turn, can undergo phosphorylation to become hypoxanthine. Hypoxanthine undergoes oxidative reactions catalyzed by xanthine oxidase (XOD), resulting in the production of xanthine. Xanthine can further undergo oxidation reactions, also catalyzed by XOD, ultimately leading to the formation of uric acid from xanthine. However, xanthine oxidase inhibitors, such as allopurinol, febuxostat, and topiroxostat, serve as first-line therapies by effectively reducing the production of uric acid from both endogenous and dietary purine sources. In the final step of purine metabolism, the enzyme uricase converts uric acid into allantoin, a highly soluble compound. While humans lack the uricase enzyme, animals naturally possess it. The therapeutic agents pegloticase and rasburicase are recombinant forms of uricase, designed to facilitate the breakdown of uric acid in humans

Fig. 3

In East Asian populations, four loci have demonstrated a significant association with serum urate levels: SLC2A9, ABCG2, SLC22A12, and MAF. Similarly, in African American populations, three loci have been identified: SLC2A9, SLC22A12, and SLC2A12. In contrast, the European population predominantly shows an association with only one locus, SLC2A9. Australian studies have identified 28 loci, encompassing all but one (SLC2A12) of those found in African American and East Asian populations. Among these diverse populations, certain loci, such as SLC2A9, ABCG2, GCKR, and SLC17A1-SLC17A4 (also known as NPT1-NPT4), exhibit stronger effects and have been consistently replicated in multiple studies

Fig. 4

Uric acid undergoes a dynamic process of elimination and reabsorption, primarily orchestrated by the kidneys (two-thirds) and the intestines (one-third). In the nephron, filtration of water and solutes occurs within the glomerular capsule, followed by tubular reabsorption, predominantly mediated by the proximal convoluted tubule. Concurrently, tubular secretions extract uric acid from peritubular capillaries, secreting it into the tubular fluid for urinary excretion. Urate transporters in renal proximal tubule epithelial cells actively mediate the secretion and reabsorption of urate, thus determining the net excretion levels from the kidney. In the renal proximal tubule, SLC22A12 (URAT1), SLC17A1 (NPT1), and SLC22A11 (OAT4) located on the apical membrane facilitate reabsorption. SLC2A9 (GLUT9), found in both the apical and basolateral membrane tubules, is a long isoform that mediates the basolateral efflux of urate back into circulation. For excretion, SLC22A6 (OAT1) and SLC22A8 (OAT3) on the basolateral membrane facilitate urate entry into the renal tubules. ABCG2 (BCRP) and SLC17A3 (NPT4), positioned on the apical side, contribute to the secretory transport of urate into the tubule lumen for urinary excretion. In intestinal metabolism, uric acid is actively secreted into the intestinal lumen primarily by the transporter ABCG2, underscoring the role of the intestines in urate homeostasis

Fig. 5

The role of uric acid in the pathogenesis of hyperuricemia and its associated diseases involves complex intracellular signaling mechanisms. Elevated intracellular uric acid levels stimulate the production of reactive oxygen species and activate multiple inflammatory signaling pathways. XO xanthine oxidase, eNOS endothelial nitric oxide synthase, MSU monosodium urate, Nrf2 Nuclear factor-erythroid 2-related factor 2, mTOR mammalian target of rapamycin complex, ERK extracellular signal-regulated kinase, AMPK AMP-activated protein kinase, IL-1β interleukin-1β, MAPK mitogen-activated protein kinases, PRAS40 Proline-Rich AKT Substrate, NF-κB nuclear factor κB, TLR Toll-like receptors, NLRP3, NOD-, LRR- and pyrin domain-containing 3, PKC Protein Kinase C, RAGE Receptor for Advanced Glycation End Products pathway