Oral Spermidine Supplementation Preserves Submandibular Gland Function After Radiotherapy: Mechanistic Insights and Use in a Phase II Randomized Clinical Trial

Abstract

Radiotherapy for head and neck cancer commonly induces salivary gland dysfunction, resulting in xerostomia that substantially impairs quality of life after treatment. To identify protective strategies, we established the irradiation-induced submandibular glands (SMG) injury mice model and performed integrated proteomic and metabolomic profiling of gland tissue and saliva. Spermidine levels were significantly altered in irradiated SMG during the postradiotherapy recovery phase. Oral spermidine supplementation restored salivary flow, preserved acinar aquaporin-5 expression, and attenuated vacuolization, apoptosis, and fibrosis in vivo; these effects were validated in SMG organoids. Single-cell RNA transcriptomic analysis further showed that spermidine increased the proportion of acinar cells, enhanced Golgi-mediated secretory gene expression, and suppressed inflammatory cytokine signaling. In the randomized, double-blind, proof-of-concept clinical trial, oral spermidine supplementation during peri-radiotherapy significantly reduced the incidence of xerostomia at 3 months compared with placebo (48.28 vs. 79.31%, p = 0.0391), while increasing salivary output and improving quality of life without serious adverse events. These findings highlight the potential of spermidine as a safe, metabolite-based strategy for preserving salivary gland function and alleviating radiation-induced xerostomia.

Keywords

clinical trial / radiotherapy / spermidine / submandibular gland injury / xerostomia

References

[1] C. Porcheri and T. A. Mitsiadis, “Physiology, Pathology and Regeneration of Salivary Glands,” Cells 8, no. 9 (2019): 976.

[2] C. Rocchi and E. Emmerson, “Mouth-Watering Results: Clinical Need, Current Approaches, and Future Directions for Salivary Gland Regeneration,” Trends in Molecular Medicine 26 (2020): 649–669.

[3] F. Martinez-Madrigal and C. Micheau, “Histology of the Major Salivary Glands,” American Journal of Surgical Pathology 13 (1989): 879–899.

[4] G. B. Proctor, “The Physiology of Salivary Secretion,” Periodontol 2000 70 (2016): 11–25.

[5] M. Little, M. Schipper, and F. Y. Feng, “Reducing Xerostomia After Chemo-IMRT for Head-and-neck Cancer: Beyond Sparing the Parotid Glands,” International Journal of Radiation and Oncology in Biology and Physics 83 (2012): 1007–1014.

[6] Z. H. Wang, C. Yan, and Z. Y. Zhang, “Impact of Salivary Gland Dosimetry on Post-IMRT Recovery of Saliva Output and Xerostomia Grade for Head-and-neck Cancer Patients Treated With or Without Contralateral Submandibular Gland Sparing: A Longitudinal Study,” International Journal of Radiation and Oncology in Biology and Physics 81 (2011): 1479–1487.

[7] D. Alterio, G. Marvaso, A. Ferrari, S. Volpe, R. Orecchia, and B. A. Jereczek-Fossa, “Modern Radiotherapy for Head and Neck Cancer,” Seminars in Oncology 46 (2019): 233–245.

[8] S. Zhang, N. Zeng, and J. Yang, “Advancements of Radiotherapy for Recurrent Head and Neck Cancer in Modern Era,” Radiation Oncology 18 (2023): 166.

[9] S. Huang, Y. Liang, N. Liu, and J. Ma, “Predictive Biomarkers for Immunotherapy in Nasopharyngeal Carcinoma: From Tumor Microenvironment to Macroenvironment,” Frontiers in Medicine 19 (2025): 721–742.

[10] H. Deng, J. Li, and L. R. Gao, “Secretory Leukocyte Peptidase Inhibitor as a Dynamic Radiotherapy Response Biomarker in Esophageal Squamous Cell Carcinoma,” MedScience, ahead of print, (2026), https://www.doi.org/10.1007/s11684-026-1211-5.

[11] J. J. Caudell, J. F. Torres-Roca, and R. J. Gillies, “The Future of Personalised Radiotherapy for Head and Neck Cancer,” The Lancet Oncology 18 (2017): e266–e273.

[12] M. Shahid Iqbal, C. Kelly, and J. Kovarik, “Palliative Radiotherapy for Locally Advanced Non-metastatic Head and Neck Cancer: A Systematic Review,” Radiotherapy and Oncology 126 (2018): 558–567.

[13] J. Castelli, J. Thariat, and K. Benezery, “Weekly Adaptive Radiotherapy vs Standard Intensity-Modulated Radiotherapy for Improving Salivary Function in Patients with Head and Neck Cancer: A Phase 3 Randomized Clinical Trial,” JAMA Oncology 9 (2023): 1056–1064.

[14] C. Paz, A. Glassey, and A. Frick, “Cancer Therapy-related Salivary Dysfunction,” Journal of Clinical Investigation 134, no. 17 (2024): e182661.

[15] C. O. Nathan, A. A. Asarkar, and P. Entezami, “Current Management of Xerostomia in Head and Neck Cancer Patients,” American Journal of Otolaryngology 44 (2023): 103867.

[16] P. Dirix, S. Nuyts, and W. Van den Bogaert, “Radiation-induced Xerostomia in Patients With Head and Neck Cancer: A Literature Review,” Cancer 107 (2006): 2525–2534.

[17] M. D. Acauan, M. A. Figueiredo, K. Cherubini, A. P. Gomes, and F. G. Salum, “Radiotherapy-induced Salivary Dysfunction: Structural Changes, Pathogenetic Mechanisms and Therapies,” Archives of Oral Biology 60 (2015): 1802–1810.

[18] A. Vissink, J. B. Mitchell, and B. J. Baum, “Clinical Management of Salivary Gland Hypofunction and Xerostomia in Head-and-neck Cancer Patients: Successes and Barriers,” International Journal of Radiation and Oncology in Biology and Physics 78 (2010): 983–991.

[19] P. Riley, A. M. Glenny, F. Hua, and H. V. Worthington, “Pharmacological Interventions for Preventing Dry Mouth and Salivary Gland Dysfunction Following Radiotherapy,” Cochrane Database of Systematic Reviews 7 (2017): Cd012744.

[20] N. H. Nicolay, R. Lopez Perez, J. Debus, and P. E. Huber, “Mesenchymal Stem Cells – A New Hope for Radiotherapy-induced Tissue Damage?,” Cancer Letters 366 (2015): 133–140.

[21] S. Pringle, R. Van Os, and R. P. Coppes, “Concise Review: Adult Salivary Gland Stem Cells and a Potential Therapy for Xerostomia,” Stem Cells 31 (2013): 613–619.

[22] M. Babu and M. Snyder, “Multi-Omics Profiling for Health,” Molecular & Cellular Proteomics 22 (2023): 100561.

[23] K. J. Karczewski and M. P. Snyder, “Integrative Omics for Health and Disease,” Nature Reviews Genetics 19 (2018): 299–310.

[24] Q. Zhao, S. Pan, and L. Zhang, “A Salivary Gland Resident Macrophage Subset Regulating Radiation Responses,” Journal of Dental Research 102 (2023): 536–545.

[25] J. Li, S. Sudiwala, and L. Berthoin, “Long-term Functional Regeneration of Radiation-damaged Salivary Glands Through Delivery of a Neurogenic Hydrogel,” Science Advances 8 (2022): eadc8753.

[26] J. G. McKendrick, G. R. Jones, and S. S. Elder, “CSF1R-dependent Macrophages in the Salivary Gland Are Essential for Epithelial Regeneration After Radiation-induced Injury,” Science Immunology 8 (2023): eadd4374.

[27] M. J. Gough, S. Sharon, M. R. Crittenden, and K. H. Young, “Using Preclinical Data to Design Combination Clinical Trials of Radiation Therapy and Immunotherapy,” Seminars in Radiation Oncology 30 (2020): 158–172.

[28] C. S. Wilhelm-Benartzi, S. Mt-Isa, F. Fiorentino, R. Brown, and D. Ashby, “Challenges and Methodology in the Incorporation of Biomarkers in Cancer Clinical Trials,” Critical Reviews in Oncology/Hematology 110 (2017): 49–61.

[29] L. G. Buss, B. A. Rheinheimer, and K. H. Limesand, “Radiation-induced Changes in Energy Metabolism Result in Mitochondrial Dysfunction in Salivary Glands,” Scientific Reports 14 (2024): 845.

[30] A. M. Laheij, C. N. Rasch, and B. W. Brandt, “Proteins and Peptides in Parotid Saliva of Irradiated Patients Compared to That of Healthy Controls Using SELDI-TOF-MS,” BMC Research Notes 8 (2015): 639.

[31] G. Li, H. Ding, and X. Yu, “Spermidine Suppresses Inflammatory DC Function by Activating the FOXO3 Pathway and Counteracts Autoimmunity,” Iscience 23 (2020): 100807.

[32] C. Valentino, B. Vigani, and I. Fedeli, “Development of Alginate-spermidine Micro/Nanogels as Potential Antioxidant and Anti-inflammatory Tool in Peripheral Nerve Injuries. Formulation Studies and Physico-chemical Characterization,” International Journal of Pharmaceutics 626 (2022): 122168.

[33] K. Freitag, N. Sterczyk, and S. Wendlinger, “Spermidine Reduces Neuroinflammation and Soluble Amyloid Beta in an Alzheimer's disease Mouse Model,” Journal of Neuroinflammation 19 (2022): 172.

[34] F. Madeo, T. Eisenberg, F. Pietrocola, and G. Kroemer, “Spermidine in Health and Disease,” Science 359 (2018): eaan2788.

[35] Y. H. Choi and H. Y. Park, “Anti-inflammatory Effects of Spermidine in Lipopolysaccharide-stimulated BV2 Microglial Cells,” Journal of Biomedical Science 19 (2012): 31.

[36] J. W. Jeong, H. J. Cha, and M. H. Han, “Spermidine Protects Against Oxidative Stress in Inflammation Models Using Macrophages and Zebrafish,” Biomolecules & therapeutics 26 (2018): 146–156.

[37] L. Ma, L. Ni, and T. Yang, “Preventive and Therapeutic Spermidine Treatment Attenuates Acute Colitis in Mice,” Journal of Agricultural and Food Chemistry 69 (2021): 1864–1876.

[38] S. J. Hofer, Y. Liang, and A. Zimmermann, “Spermidine-induced Hypusination Preserves Mitochondrial and Cognitive Function During Aging,” Autophagy 17 (2021): 2037–2039.

[39] S. J. Hofer, I. Daskalaki, and M. Bergmann, “Spermidine Is Essential for Fasting-mediated Autophagy and Longevity,” Nature Cell Biology 26 (2024): 1571–1584.

[40] S. J. Hofer, A. K. Simon, M. Bergmann, T. Eisenberg, G. Kroemer, and F. Madeo, “Mechanisms of Spermidine-induced Autophagy and Geroprotection,” Nature Aging 2 (2022): 1112–1129.

[41] F. B. Coeli-Lacchini, G. da Silva, and M. Belentani, “Spermidine Suppresses Oral Carcinogenesis Through Autophagy Induction, DNA Damage Repair, and Oxidative Stress Reduction,” American Journal of Pathology 193 (2023): 2172–2181.

[42] K. Yoshida, Z. Liu, and Y. Kubo, “Spermidine Alleviates Thymopoiesis Defects and Aging of the Peripheral T-cell Population in Mice After Radiation Exposure,” Experimental Gerontology 199 (2025): 112646.

[43] J. Li and Y. Wang, “Golgi Metal Ion Homeostasis in Human Health and Diseases,” Cells 11, no. 2 (2022): 289.

[44] R. Benyair, A. Eisenberg-Lerner, and Y. Merbl, “Maintaining Golgi Homeostasis: A Balancing Act of Two Proteolytic Pathways,” Cells 11, no. 5 (2022): 780.

[45] T. Dusabimana, J. Je, S. P. Yun, H. J. Kim, H. Kim, and S. W. Park, “GOLPH3 promotes Endotoxemia-induced Liver and Kidney Injury Through Golgi Stress-mediated Apoptosis and Inflammatory Response,” Cell Death & Disease 14 (2023): 458.

[46] J. Gao, A. Gao, W. Liu, and L. Chen, “Golgi Stress Response: A Regulatory Mechanism of Golgi Function,” Biofactors 47 (2021): 964–974.

[47] S. E. Farber-Katz, H. C. Dippold, and M. D. Buschman, “DNA Damage Triggers Golgi Dispersal via DNA-PK and GOLPH3,” Cell 156 (2014): 413–427.

[48] X. Meng, C. S. Wijaya, Q. Shao, and S. Xu, “Triggered Golgi Membrane Enrichment Promotes PtdIns(4,5)P2 Generation for Plasma Membrane Repair,” Journal of Cell Biology 222, no. 8 (2023): e202303017.

[49] M. Martins, A. S. Fernandes, and N. Saraiva, “GOLGI: Cancer Cell Fate Control,” International Journal of Biochemistry & Cell Biology 145 (2022): 106174.

[50] M. F. Rahman, A. H. Kurlovs, and M. Vodnala, “Immune Disease Dialogue of Chemokine-based Cell Communications as Revealed by Single-cell RNA Sequencing Meta-analysis,” Frontiers in Systems Biology 4 (2024): 1466368.

[51] G. Li, Z. Yang, and C. Yang, “Single-cell RNA Sequencing Reveals Cell-cell Communication and Potential Biomarker in Sepsis and Septic Shock Patients,” International Immunopharmacology 132 (2024): 111938.

[52] M. Langner, I. Mateska, and N. Bechmann, “Liquid Chromatography-tandem Mass Spectrometry Based Quantification of Arginine Metabolites Including Polyamines in Different Sample Matrices,” Journal of Chromatography A 1671 (2022): 463021.

[53] M. Szydlowska, G. Lasky, and S. Oldham, “Restoring Polyamine Levels by Supplementation of Spermidine Modulates Hepatic Immune Landscape in Murine Model of NASH,” Biochimica et Biophysica Acta - Molecular Basis of Disease 1869 (2023): 166697.

[54] B. Guan, C. Li, and Y. Yang, “Effect of Spermidine on Radiation-induced Long-term Bone Marrow Cell Injury,” International Immunopharmacology 114 (2023): 109557.

[55] I. Tirosh, B. Izar, and S. M. Prakadan, “Dissecting the Multicellular Ecosystem of Metastatic Melanoma by Single-cell RNA-seq,” Science 352 (2016): 189–196.

[56] S. Hopewell, A. W. Chan, and G. S. Collins, “CONSORT 2025 Statement: Updated Guideline for Reporting Randomised Trials,” Lancet, ahead of print, (2025), https://www.doi.org/10.1016/S0140-6736(25)00672-5.

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