Loss of Neuropeptide Y Signaling Accompanies the Neural-to-Mesenchymal Transcriptional Transition in Glioblastoma: A Multi-Scale Transcriptomic Analysis

Arshad, Fareeha; Abualsaud, Nouran; Akbar, Arshiya; Khan, Mohammed Imran; Rasheed, Bushra; Hussain, Adnan; Alghamdi, Fahad Ali; Farrash, Faisal Abdulhameed; Aroke, Edwin N.; Freij, Khalid Walid; Arora, Itika; Yaqinuddin, Ahmed

doi:10.3390/ijms27136068

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Loss of Neuropeptide Y Signaling Accompanies the Neural-to-Mesenchymal Transcriptional Transition in Glioblastoma: A Multi-Scale Transcriptomic Analysis

by

Fareeha Arshad

¹,

Nouran Abualsaud

²,

Arshiya Akbar

¹,

Mohammed Imran Khan

³,

Bushra Rasheed

¹,

Adnan Hussain

³,

Fahad Ali Alghamdi

³,

Faisal Abdulhameed Farrash

⁴

,

Edwin N. Aroke

⁵

,

Khalid Walid Freij

⁵

,

Itika Arora

^1,* and

Ahmed Yaqinuddin

^1,*

¹

College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia

²

King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh 11426, Saudi Arabia

³

King Faisal Specialist Hospital and Research Center, Jeddah 23433, Saudi Arabia

⁴

King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia

⁵

Department of Acute, Chronic & Continuing Care, School of Nursing, University of Alabama at Birmingham, Birmingham, AL 35294, USA

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2026, 27(13), 6068; https://doi.org/10.3390/ijms27136068

Submission received: 20 April 2026 / Revised: 19 June 2026 / Accepted: 23 June 2026 / Published: 6 July 2026

(This article belongs to the Special Issue Molecular and Cellular Research on the Glioma and Tumor Microenvironment)

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Abstract

Neuropeptide Y [NPY; encoded by the NPY gene] is a widely expressed 36-amino-acid neuropeptide that regulates neuronal function, vascular regulation, and immune regulation; its role in glioblastoma [GBM] remains incompletely characterized. We performed an integrative in silico multi-scale transcriptomic analysis combining bulk RNA-sequencing of IDH-wildtype GBM [n = 169] and lower-grade glioma [n = 510] surgical resections from TCGA, normal cortical tissue from GTEx [n = 207], and four independent GEO validation cohorts of surgical GBM and non-tumor brain specimens [GSE4290, GSE50161, GSE131928 scRNA-seq of ~20,426 cells from 28 patients, and GSE194329 10X Visium spatial transcriptomics from five patients], along with survival modeling, pathway enrichment, single-cell RNA sequencing, spatial transcriptomics, and cell–cell communication analysis. NPY and its principal receptor, NPY1R, were significantly downregulated in GBM, while genes associated with hypoxia, angiogenesis, invasion, and immune suppression were upregulated. Single-cell analysis showed that NPY-axis transcript expression was elevated in neural progenitor-like populations. In contrast, hypoxia and metabolic programs were concentrated in mesenchymal tumors and stromal compartments, indicating distinct cellular contexts. Spatial analysis revealed a weak and heterogeneous relationship between NPY and hypoxia signatures, with substantial inter-patient variability and no significant global spatial cross-correlation. These findings indicate that loss of NPY signaling is a consistent feature of GBM and is associated with hypoxia-driven tumor states, while the spatial relationship between NPY and hypoxia appears weak, heterogeneous, and patient-specific.

Keywords: angiogenesis; gene expression; glioblastoma; hypoxia; immune suppression; neuropeptide Y; single-cell RNA sequencing; spatial transcriptomics; transcriptomic analysis; tumor microenvironment

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MDPI and ACS Style

Arshad, F.; Abualsaud, N.; Akbar, A.; Khan, M.I.; Rasheed, B.; Hussain, A.; Alghamdi, F.A.; Farrash, F.A.; Aroke, E.N.; Freij, K.W.; et al. Loss of Neuropeptide Y Signaling Accompanies the Neural-to-Mesenchymal Transcriptional Transition in Glioblastoma: A Multi-Scale Transcriptomic Analysis. Int. J. Mol. Sci. 2026, 27, 6068. https://doi.org/10.3390/ijms27136068

AMA Style

Arshad F, Abualsaud N, Akbar A, Khan MI, Rasheed B, Hussain A, Alghamdi FA, Farrash FA, Aroke EN, Freij KW, et al. Loss of Neuropeptide Y Signaling Accompanies the Neural-to-Mesenchymal Transcriptional Transition in Glioblastoma: A Multi-Scale Transcriptomic Analysis. International Journal of Molecular Sciences. 2026; 27(13):6068. https://doi.org/10.3390/ijms27136068

Chicago/Turabian Style

Arshad, Fareeha, Nouran Abualsaud, Arshiya Akbar, Mohammed Imran Khan, Bushra Rasheed, Adnan Hussain, Fahad Ali Alghamdi, Faisal Abdulhameed Farrash, Edwin N. Aroke, Khalid Walid Freij, and et al. 2026. "Loss of Neuropeptide Y Signaling Accompanies the Neural-to-Mesenchymal Transcriptional Transition in Glioblastoma: A Multi-Scale Transcriptomic Analysis" International Journal of Molecular Sciences 27, no. 13: 6068. https://doi.org/10.3390/ijms27136068

APA Style

Arshad, F., Abualsaud, N., Akbar, A., Khan, M. I., Rasheed, B., Hussain, A., Alghamdi, F. A., Farrash, F. A., Aroke, E. N., Freij, K. W., Arora, I., & Yaqinuddin, A. (2026). Loss of Neuropeptide Y Signaling Accompanies the Neural-to-Mesenchymal Transcriptional Transition in Glioblastoma: A Multi-Scale Transcriptomic Analysis. International Journal of Molecular Sciences, 27(13), 6068. https://doi.org/10.3390/ijms27136068

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Loss of Neuropeptide Y Signaling Accompanies the Neural-to-Mesenchymal Transcriptional Transition in Glioblastoma: A Multi-Scale Transcriptomic Analysis

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