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Ghrelin-induced neuronal NPY promotes brain metastasis in lung cancer patients with low BMI

Author

Listed:
  • Abhishek Tyagi

    (Wake Forest University School of Medicine)

  • Shih-Ying Wu

    (Wake Forest University School of Medicine)

  • Jee-Won Kim

    (Wake Forest University School of Medicine)

  • Ravindra Pramod Deshpande

    (Wake Forest University School of Medicine)

  • Kerui Wu

    (Joint School of Nanoscience & Nanoengineering)

  • Eleanor C. Smith

    (Wake Forest University School of Medicine)

  • Giuseppe L. Banna

    (University of Portsmouth)

  • Kounosuke Watabe

    (Wake Forest University School of Medicine)

Abstract

Obesity is a known risk factor for many cancers, yet recent studies reveal a paradoxical association between low body mass index (BMI) and increased brain metastasis in lung cancer—referred to as the “obesity paradox,” with unclear molecular mechanism(s). Here, we show a significantly higher incidence of brain metastasis in low-BMI lung cancer patients compared to those with high-BMI or other cancer brain metastasis in a pan-analysis of 7628 patients. Mechanistically, low BMI activates ghrelin-GHSR signaling, increasing neuronal neuropeptide Y (NPY) secretion, which promotes tumor metabolic reprogramming via NPY-Y5R, facilitating brain colonization. Elevated plasma ghrelin levels in cancer-free low-BMI subjects suggest its potential as a prognostic biomarker for predicting brain metastasis. Notably, targeting NPY-Y5R or reversing low BMI effectively suppresses brain metastasis, supporting its pro-metastatic role. These findings provide a strong rationale for developing targeted interventions to treat or prevent brain metastasis in lung cancer patients with low BMI.

Suggested Citation

  • Abhishek Tyagi & Shih-Ying Wu & Jee-Won Kim & Ravindra Pramod Deshpande & Kerui Wu & Eleanor C. Smith & Giuseppe L. Banna & Kounosuke Watabe, 2025. "Ghrelin-induced neuronal NPY promotes brain metastasis in lung cancer patients with low BMI," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60730-4
    DOI: 10.1038/s41467-025-60730-4
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