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

• Published in: Nature communications Vol. 16; no. 1; pp. 5608 - 18
• Main Authors: Tyagi, Abhishek, Wu, Shih-Ying, Kim, Jee-Won, Deshpande, Ravindra Pramod, Wu, Kerui, Smith, Eleanor C., Banna, Giuseppe L., Watabe, Kounosuke
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/31; 14/5; 14/63; 38/109; 38/88; 42/41; 631/67/1612/1350; 631/67/1857; 631/67/2327; 631/67/322; 64/60; 82/51; Aged; Animals; Biomarkers; Body Mass Index; Body size; Brain; Brain cancer; Brain Neoplasms - metabolism; Brain Neoplasms - secondary; Brain tumors; Calories; Cell growth; Cell Line, Tumor; Female; Ghrelin; Ghrelin - blood; Ghrelin - metabolism; Growth hormones; Humanities and Social Sciences; Humans; Immunohistochemistry; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Medical prognosis; Melanoma; Metastases; Metastasis; Mice; Middle Aged; Molecular modelling; Mortality; multidisciplinary; Neurons - metabolism; Neuropeptide Y; Neuropeptide Y - genetics; Neuropeptide Y - metabolism; Obesity; Obesity - complications; Obesity - metabolism; Paradoxes; Physiology; Receptors, Ghrelin - metabolism; Receptors, Neuropeptide Y - metabolism; Risk factors; Science; Science (multidisciplinary); Secretion; Signal Transduction; Tumor cells; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-60730-4

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. Low body mass index (BMI) is associated with increased brain metastasis risk in lung cancer patients. Here, the authors report that low-BMI increases neuronal secretion of neuropeptide Y (NPY), thereby activating the NPY receptor on lung tumor cells, leading to tumor metabolic reprogramming and brain metastasis.