{
  "abstract": "Background: BTB domain containing 9 (BTBD9) is among the most reproducible genetic risk factors for sleep-related disorders, yet its molecular function in sleep regulation remains unclear. Here, we aimed to define the downstream substrate, core brain region, and molecular mechanism through which BTBD9 regulates sleep–wake homeostasis.\n\nMethods: Population-scale genomic and brain expression quantitative trait locus (eQTL) datasets were integrated to infer the direction of BTBD9-associated genetic risk in sleep-related traits. Basal forebrain-specific neuronal manipulation of Btbd9 was combined with electroencephalography/electromyography (EEG/EMG)-based sleep analysis and fiberphotomerty to define the relevant brain locus and functional output. Ubiquitinomics, protein interaction, ubiquitination, and enzymatic assays were used to identify BTBD9-regulated substrates and determine how BTBD9-dependent modification affects metabolic enzyme activity. Basal forebrain-specific genetic disruption, receptor pharmacology, and adeno-associated virus (AAV)-delivered interfering peptides were further applied to test pathway necessity and reversibility in vivo.\n\nResults: human genetic analyses showed that BTBD9 variants associated with higher expression predicted a pro-arousal tendency. Consistently, neuron-specific deletion of Btbd9 in the mouse basal forebrain increased non-rapid eye movement (NREM) sleep and extracellular adenosine levels. Mechanistically, IMPDH2, the rate-limiting enzyme in de novo purine biosynthesis, was identified as a substrate of the Cullin-RING E3 ubiquitin ligase 3 (CRL3)BTBD9 ubiquitin ligase. BTBD9-mediated ubiquitination at IMPDH2 lysine 195 (K195) relieved guanosine triphosphate (GTP)-dependent allosteric inhibition, thereby limiting adenosine accumulation and sleep pressure. Basal forebrain neuronal knockout of Impdh2 recapitulated the sleep-promoting effect of Btbd9 deletion, whereas adenosine A1 receptor (A1R) blockade attenuated this phenotype. AAV-delivered interfering peptides targeting the BTBD9–IMPDH2 interaction reduced IMPDH2 ubiquitination, elevated adenosine levels, increased NREM sleep, and rescued BTBD9 overexpression-induced abnormal wakefulness in vivo.\n\nConclusions: These findings identify a BTBD9–IMPDH2–adenosine pathway that links human genetic risk to basal forebrain control of sleep homeostasis. By defining BTBD9 as a molecular regulator of purine metabolism, this study provides a mechanistic framework for understanding and potentially targeting BTBD9-related sleep dysregulation.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12964-026-03117-2.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Otolaryngology-Head and Neck Surgery & Center of Sleep Medicine, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai Jiao Tong University School of Medicine Affiliated Sixth People’s Hospital, Shanghai, 200233 China",
    "Center for Sleep Monitoring and Respiratory Therapy Technology, Institute of Medical Equipment and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233 China",
    "Department of Otolaryngology & Head and Neck Surgery, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, No. 197 Ruijin 2nd Road, Shanghai, 200025 China",
    "Department of Anatomy and Histoembryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032 China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Zhenfei Gao"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Niannian Li"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jiawei Feng"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jinhong Shen"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Haolin Yuan"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Kejia Wu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xu Xu"
    },
    {
      "affs": [
        2
      ],
      "name": "Yuenan Liu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yiming Hu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Shengming Wang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Hui Wang"
    },
    {
      "affs": [
        3
      ],
      "name": "Xiangshan Yuan"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jian Guan"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Feng Liu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Shankai Yin"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/f86eqffkfma3f.bib",
  "cited_by": 0,
  "doi": "10.1186/s12964-026-03117-2",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13711913/",
  "id": "f86eqffkfma3f",
  "issns": [
    "1478-811X"
  ],
  "landing_url": "https://doi.org/10.1186/s12964-026-03117-2",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2805|Sleep and Wakefulness Research"
    ]
  ],
  "openalex": "W7171831451",
  "pdf_url": null,
  "pmcid": "PMC13711913",
  "pmid": "42947189",
  "published": "2026-07-30",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/f86eqffkfma3f.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:22:36Z",
      "native_id": "PMC13711913",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s12964-026-03117-2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2805|Sleep and Wakefulness Research",
      "subfield": "neuroscience"
    }
  ],
  "title": "BTBD9-driven IMPDH2 ubiquitination governs sleep homeostasis by gating adenosine metabolism in the basal forebrain",
  "title_text": "BTBD9-driven IMPDH2 ubiquitination governs sleep homeostasis by gating adenosine metabolism in the basal forebrain",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:22:36Z",
  "url": "https://research.draconitic.com/paper/f86eqffkfma3f",
  "venue": "Cell Communication and Signaling : CCS",
  "versions": []
}