{
  "abstract": "Background: The hominoid loss of urate oxidase (uricase) represents a classic evolutionary trade-off, shifting uric acid (UA) from a metabolic waste product to a potent physiological modulator. In modern metabolic environments, however, this adaptation drives hyperuricemia and gout, transforming UA into a primary pathological substrate. Objective: This review aims to dissect the molecular architecture and biophysical networks of the renal and intestinal urate transportosome, delineate the dual intracellular/extracellular \"urate paradox,\" and synthesize genotype-based pharmacogenetic strategies to achieve personalized clinical management. Mechanistic Insights: During the Miocene epoch, inactivating pseudogenization of the UOX gene fixed a novel metabolic phenotype characterized by fructose-driven lipid deposition and enhanced antioxidant protection. Structurally, systemic urate homeostasis is strictly governed by a macromolecular interactome assembled by the four-domain scaffold protein PDZK1 on the epithelial apical membrane. Pathogenic gain-of-function variants in reabsorption facilitators (SLC22A12/URAT1, SLC2A9/GLUT9) or loss-of-function mutations in the efflux pump (ABCG2/BCRP) disrupt this delicate vector kinetics. Within the extracellular space, soluble urate acts as a critical hydrophilic radical scavenger. Paradoxically, upon URAT1/GLUT9-mediated internalization or intracellular supersaturation, intracellular urate triggers a pro-oxidant cascade mediated by NADPH oxidase (NOX4) activation and mitochondrial electron transport chain decoupling. This chronic cellular stress activates downstream p38 MAPK and NF-κB signaling pathways, driving localized endothelial injury and macrovascular inflammation, while crystalline monosodium urate (MSU) orchestrates NLRP3 inflammasome assembly in macrophages. Pharmacogenetic Implications: Striking ethno-geographic heterogeneity dictates immediate clinical stratification. The HLA-B*58:01 allele, an absolute molecular contraindication for allopurinol due to life-threatening severe cutaneous adverse reactions (SCARs), exhibits a critical genetic gradient in northern and eastern Eurasian populations, surging from under 1% in ethnic Caucasians to over 10% in indigenous populations of East/North Asian ancestry. Furthermore, structural defects in ABCG2 (such as the p.Q141K variant) alter the ATP-binding cassette domain, inducing standard allopurinol resistance and elevated statin exposure, which mandates a therapeutic pivot toward selective xanthine oxidase inhibitors (febuxostat) or precision uricosurics (benzbromarone, dotinurad) matched to the patient's interactive network profile. Conclusions: Transitioning from generalized epidemiological guidelines to a comprehensive \"transportosome genetic passport\" is a fundamental prerequisite for predicting single-nucleotide polymorphism (SNP)-driven therapeutic responses and mitigating visceral complications.",
  "abstract_shown": true,
  "affiliations": [
    "N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russia.",
    "Federal State Budgetary Institution \"Centre for Strategic Planning and Management of Biomedical Health Risks\" of the Federal Medical and Biological Agency, Pogodinskaya Str. 10/1, Moscow 119121, Russia.",
    "JSC \"Medsi Group of Companies\", Michurinsky Prospekt 56/1, Moscow 119192, Russia.",
    "Department of Medical Genetics and Fundamental Medicine, Bashkir State Medical University, Ufa 450008, Russia.",
    "Department of Propaedeutics of Internal Diseases No. 2, Institute of Clinical Medicine, Pirogov Russian National Research Medical University, Moscow 117513, Russia."
  ],
  "article_type": "review article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Lilya U Dzhemileva",
      "orcid": "0000-0003-3315-4746"
    },
    {
      "affs": [
        0
      ],
      "name": "Vladimir A D'yakonov",
      "orcid": "0000-0002-7787-5054"
    },
    {
      "affs": [
        2,
        4
      ],
      "name": "Sergey N Marshala",
      "orcid": "0009-0004-9738-7447"
    },
    {
      "affs": [
        3
      ],
      "name": "Elza Khusnutdinova",
      "orcid": "0000-0003-2987-3334"
    },
    {
      "affs": [
        1
      ],
      "name": "Andrey A Deviatkin",
      "orcid": "0000-0003-0789-4601"
    },
    {
      "affs": [
        1
      ],
      "name": "German A Shipulin",
      "orcid": "0000-0002-3668-6601"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0sm2yfbcpkhfr.bib",
  "cited_by": 0,
  "doi": "10.3390/medsci14060612",
  "fulltext_url": "https://europepmc.org/articles/PMC13707038",
  "id": "0sm2yfbcpkhfr",
  "issns": [
    "2076-3271"
  ],
  "landing_url": "https://europepmc.org/article/MED/42930531",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2727|Gout, Hyperuricemia, Uric Acid"
    ]
  ],
  "openalex": "W7214609653",
  "pdf_url": "https://europepmc.org/articles/PMC13707038?pdf=render",
  "pmcid": "PMC13707038",
  "pmid": "42930531",
  "published": "2026-09-28",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/0sm2yfbcpkhfr.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:01Z",
      "native_id": "MED:42930531",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42930531"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2727|Gout, Hyperuricemia, Uric Acid",
      "subfield": "general"
    }
  ],
  "title": "The Human Urate Transportosome: Evolutionary Dynamics, Molecular Mechanisms, and Pharmacogenetic Perspectives.",
  "title_text": "The Human Urate Transportosome: Evolutionary Dynamics, Molecular Mechanisms, and Pharmacogenetic Perspectives.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:22:01Z",
  "url": "https://research.draconitic.com/paper/0sm2yfbcpkhfr",
  "venue": "Medical sciences (Basel, Switzerland)",
  "versions": []
}