Therapeutic Music as a Neuroimmune–Metabolic Modulator in NAFLD: A Spleen‑Centered Working Hypothesis

Giovanni Tarantino

doi:10.62425/rtpharma.1969941

Therapeutic Music as a Neuroimmune–Metabolic Modulator in NAFLD: A Spleen‑Centered Working Hypothesis

Abstract

Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease, is frequently accompanied by depression and chronic psychological stress that can worsen metabolic dysfunction, promoting NAFLD progression. Given the current limitations of pharmacological treatments for NAFLD, specifically their high cost, potential for adverse side effects, and the lack of long-term data, there is an urgent clinical need for accessible, safe, and cost-effective interventions. Therapeutic music functions as a non-invasive neurocognitive intervention capable of attenuating hypothalamic-pituitary-adrenal axis hyperactivation, restoring parasympathetic tone, and rebalancing immune regulation. These neural and endocrine pathways converge directly on the spleen, a critical immunometabolic nexus translating neuroautonomic signals into systemic inflammatory outputs. Structurally predictable and emotionally engaging acoustic stimuli, such as compositions reminiscent of The Beatles, optimize dopaminergic circuit engagement and alleviate affect-driven inflammatory amplification. This review provides an exploratory, hypothesis-generating delineation of the molecular and physiological networks through which targeted music therapy modulates splenic function. Music therapy emerges not as an ancillary wellness tool, but as a mechanistically grounded intervention at the intersection of neuroimmunology, metabolic medicine, and hepatology, warranting rigorous evaluation in controlled trials.

Keywords

Supporting Institution

NA

Ethical Statement

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References

Adiasto, K., Beckers, D. G. J., van Hooff, M. L. M., Roelofs, K., & Geurts, S. A. E. (2022). Music listening and stress recovery in healthy individuals: A systematic review with meta-analysis of experimental studies. PLoS ONE, 17(6), e0270031. https://doi.org/10.1371/journal.pone.0270031
Altenmüller, E., & Schlaug, G. (2015). Apollo’s gift: New aspects of neurologic music therapy. Progress in Brain Research, 217, 237–252. https://doi.org/10.1016/bs.pbr.2014.11.029
Angelucci, F., Ricci, E., Padua, L., Sabino, A., & Tonali, P. A. (2007). Music exposure differentially alters the levels of brain-derived neurotrophic factor and nerve growth factor in the mouse hypothalamus. Neuroscience Letters, 429(2–3), 152–155. https://doi.org/10.1016/j.neulet.2007.10.005
Bekhbat, M., Drake, J., Reed, E. C., Lauten, T. H., Natour, T., Vladimirov, V. I., & Case, A. J. (2023). Repeated social defeat stress leads to immunometabolic shifts in innate immune cells of the spleen. Brain, Behavior, & Immunity-Health, 34, 100690. https://doi.org/10.1016/j.bbih.2023.100690
Bradt, J., Dileo, C., Myers-Coffman, K., & Biondo, J. (2021). Music interventions for improving psychological and physical outcomes in people with cancer. The Cochrane Database of Systematic Reviews, 2021(10), CD006911. https://doi.org/10.1002/14651858.CD006911.pub4
Chamakioti, M., Chrousos, G. P., Kassi, E., Vlachakis, D., & Yapijakis, C. (2024). Stress-related roles of exosomes and exosomal miRNAs in common neuropsychiatric disorders. International Journal of Molecular Sciences, 25(15), 8256. https://doi.org/10.3390/ijms25158256
Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008). From inflammation to sickness and depression: When the immune system subjugates the brain. Nature Reviews Neuroscience, 9(1), 46–56. https://doi.org/10.1038/nrn2297
Do, A., Zahrawi, F., & Mehal, W. (2025). Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH). Nature Reviews Drug Discovery, 24(2), 171–189. https://doi.org/10.1038/s41573-024-01084-2

Dong, J., & Qu, Y. (2024). Therapeutic effect of music therapy on patients with end-stage cancer: A retrospective study. Noise & Health, 26(121), 82–87. https://doi.org/10.4103/nah.nah_104_23
Engler, H., Engler, A., Bailey, M. T., & Sheridan, J. F. (2005). Tissue-specific alterations in the glucocorticoid sensitivity of immune cells following repeated social defeat in mice. Journal of Neuroimmunology, 163(1–2), 110–119. https://doi.org/10.1016/j.jneuroim.2005.03.002
Fancourt, D., Ockelford, A., & Belai, A. (2014). The psychoneuroimmunological effects of music: A systematic review and a new model. Brain, Behavior, and Immunity, 36, 15–26. https://doi.org/10.1016/j.bbi.2013.10.014
Farley, M. J., Boytar, A. N., Adlard, K. N., Salisbury, C. E., Hart, N. H., Schaumberg, M. A., Jenkins, D. G., & Skinner, T. L. (2024). Interleukin-15 and high-intensity exercise: Relationship with inflammation, body composition and fitness in cancer survivors. The Journal of Physiology, 602(20), 5203–5215. https://doi.org/10.1113/JP286043
Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M., & Sanyal, A. J. (2018). Mechanisms of NAFLD development and therapeutic strategies. Nature Medicine, 24(7), 908–922. https://doi.org/10.1038/s41591-018-0104-9
Fu, Y., Wu, K., Zhuang, J., Chen, Y., Jia, L., Luo, Z., & Sun, R. (2025). Music therapy in modulating immune responses and enhancing cancer treatment outcomes. Frontiers in Immunology, 16, 1639047. https://doi.org/10.3389/fimmu.2025.1639047
Healy, K. L., Morris, A. R., & Liu, A. C. (2021). Circadian synchrony: Sleep, nutrition, and physical activity. Frontiers in Network Physiology, 1, 732243. https://doi.org/10.3389/fnetp.2021.732243
Kang, D., Zhao, D., Ryu, S., Guallar, E., Cho, J., Lazo, M., Shin, H., Chang, Y., & Sung, E. (2020). Author correction: Perceived stress and non-alcoholic fatty liver disease in apparently healthy men and women. Scientific Reports, 10(1), 21978. https://doi.org/10.1038/s41598-020-78911-0
Khalafi, M., Maleki, A. H., Symonds, M. E., Sakhaei, M. H., Rosenkranz, S. K., Ehsanifar, M., Korivi, M., & Liu, Y. (2024). Interleukin-15 responses to acute and chronic exercise in adults: A systematic review and meta-analysis. Frontiers in Immunology, 14, 1288537. https://doi.org/10.3389/fimmu.2023.1288537
Koelsch, S., Fritz, T., von Cramon, D. Y., Müller, K., & Friederici, A. D. (2006). Investigating emotion with music: An fMRI study. Human Brain Mapping, 27(3), 239–250. https://doi.org/10.1002/hbm.20180
Koelsch, S., Skouras, S., & Lohmann, G. (2018). The auditory cortex hosts network nodes influential for emotion processing: An fMRI study on music-evoked fear and joy. PLoS ONE, 13(1), e0190057. https://doi.org/10.1371/journal.pone.0190057
Krenkel, O., & Tacke, F. (2017). Liver macrophages in tissue homeostasis and disease. Nature Reviews Immunology, 17(5), 306–321. https://doi.org/10.1038/nri.2017.11
Kuhn, D. (2002). The effects of active and passive participation in musical activity on the immune system as measured by salivary immunoglobulin A (SIgA). Journal of Music Therapy, 39(1), 30–39. https://doi.org/10.1093/jmt/39.1.30
Kulinski, J., Ofori, E. K., Visotcky, A., Smith, A., Sparapani, R., & Fleg, J. L. (2022). Effects of music on the cardiovascular system. Trends in Cardiovascular Medicine, 32(6), 390–398. https://doi.org/10.1016/j.tcm.2021.06.004
Li, X., Wang, L., Cheng, X., Li, M., & Chen, J. (2026). Circadian disruption aggravates non-alcoholic fatty liver disease by activating RIPK1-RIPK3-MLKL axis in mice. Scientific Reports, 16, 2817. https://doi.org/10.1038/s41598-025-32711-6
Meda, S., Gyamfi, J., Patel, K., Islam, F., Vieira, D., Nyame, S., Ruan, C., Boradia, K., Chhetri, H., Thunga, S., Adenikinju, D., Amesimeku, E., Cohen, A., Opeyemi, J., Ojo, T., Chirinos, C., Williams, O., Ogedegbe, O., & Peprah, E. (2024). Assessment of musical interventions and its effect on blood pressure among United States populations: A systematic review and meta-analysis. Frontiers in Cardiovascular Medicine, 11, 1405455. https://doi.org/10.3389/fcvm.2024.1405455
Mehdi, S. F., Pusapati, S., Khenhrani, R. R., Farooqi, M. S., Sarwar, S., Alnasarat, A., Mathur, N., Metz, C. N., LeRoith, D., Tracey, K. J., Yang, H., Brownstein, M. J., & Roth, J. (2022). Oxytocin and related peptide hormones: Candidate anti-inflammatory therapy in early stages of sepsis. Frontiers in Immunology, 13, 864007. https://doi.org/10.3389/fimmu.2022.864007
Nakamura, Y., Matsumoto, H., Wu, C. H., Fukaya, D., Uni, R., Hirakawa, Y., Katagiri, M., Yamada, S., Ko, T., Nomura, S., Wada, Y., Komuro, I., Nangaku, M., Inagi, R., & Inoue, T. (2023). Alpha 7 nicotinic acetylcholine receptor signaling boosts cell-cell interactions in macrophages effecting anti-inflammatory and organ protection. Communications Biology, 6(1), 666. https://doi.org/10.1038/s42003-023-05051-2
Nance, D. M., & Sanders, V. M. (2007). Autonomic innervation and regulation of the immune system (1987–2007). Brain, Behavior, and Immunity, 21(6), 736–745. https://doi.org/10.1016/j.bbi.2007.03.008O’
O’Neill, L. A. J., & Artyomov, M. N. (2019). Itaconate: The poster child of metabolic reprogramming in macrophage function. Nature Reviews Immunology, 19(5), 273–281. https://doi.org/10.1038/s41577-019-0128-5
Ooishi, Y., Mukai, H., Watanabe, K., Kawato, S., & Kashino, M. (2017). Increase in salivary oxytocin and decrease in salivary cortisol after listening to relaxing slow-tempo and exciting fast-tempo music. PLoS ONE, 12(12), e0189075. https://doi.org/10.1371/journal.pone.0189075
Pariante, C. M., & Lightman, S. L. (2008). The HPA axis in major depression: Classical theories and new developments. Trends in Neurosciences, 31(9), 464–468. https://doi.org/10.1016/j.tins.2008.06.006
Pavlov, V. A., & Tracey, K. J. (2012). The vagus nerve and the inflammatory reflex—Linking immunity and metabolism. Nature Reviews Endocrinology, 8(12), 743–754. https://doi.org/10.1038/nrendo.2012.189
Pope, V. C., Soliński, M., Lambiase, P. D., & Chew, E. (2025). High blood pressure inhibits cardiovascular responsiveness to expressive classical music. Scientific Reports, 15(1), 10908. https://doi.org/10.1038/s41598-025-94341-2
Qian, C., Wang, J., & Cao, X. (2024). Splenic nociceptive neural connection promotes humoral immunity. Trends in Neurosciences, 47(12), 968–970. https://doi.org/10.1016/j.tins.2024.09.008
Rakotoarivelo, V., Mayer, T. Z., Simard, M., Flamand, N., & Di Marzo, V. (2024). The impact of the CB2 cannabinoid receptor in inflammatory diseases: An update. Molecules, 29(14), 3381. https://doi.org/10.3390/molecules29143381
Saskovets, M., Saponkova, I., & Liang, Z. (2025). Effects of sound interventions on the mental stress response in adults: Scoping review. JMIR Mental Health, 12, e69120. https://doi.org/10.2196/69120
Salimpoor, V. N., van den Bosch, I., Kovacevic, N., McIntosh, A. R., Dagher, A., & Zatorre, R. J. (2013). Interactions between the nucleus accumbens and auditory cortices predict music reward value. Science, 340(6129), 216–219. https://doi.org/10.1126/science.1231059
Shea, S., Lionis, C., Kite, C., Atkinson, L., Chaggar, S. S., Randeva, H. S., & Kyrou, I. (2021). Non-alcoholic fatty liver disease (NAFLD) and potential links to depression, anxiety, and chronic stress. Biomedicines, 9(11), 1697. https://doi.org/10.3390/biomedicines9111697
Silverman, M. N., & Sternberg, E. M. (2012). Glucocorticoid regulation of inflammation and its functional correlates: From HPA axis to glucocorticoid receptor dysfunction. Annals of the New York Academy of Sciences, 1261(1), 55–63. https://doi.org/10.1111/j.1749-6632.2012.06633.x
Simon, T., Kirk, J., Dolezalova, N., Guyot, M., Panzolini, C., Bondue, A., Lavergne, J., Hugues, S., Hypolite, N., Saeb-Parsy, K., Perkins, J., Macia, E., Sridhar, A., Vervoordeldonk, M. J., Glaichenhaus, N., Donegá, M., & Blancou, P. (2023). The cholinergic anti-inflammatory pathway inhibits inflammation without lymphocyte relay. Frontiers in Neuroscience, 17, 1125492. https://doi.org/10.3389/fnins.2023.1125492
Smith, P. M., Howitt, M. R., Panikov, N., Michaud, M., Gallini, C. A., Bohlooly-Y, M., Glickman, J. N., & Garrett, W. S. (2013). The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science, 341(6145), 569–573. https://doi.org/10.1126/science.1241165
Su, Y., Lin, S., She, L., Xiong, J., Ding, Y., Zhang, Y., & Chen, Y. (2025). Major depression as a catalyst for nonalcoholic fatty liver disease: Insights from a comprehensive Mendelian randomization study. Canadian Journal of Gastroenterology and Hepatology, 2025, Article 6632867. https://doi.org/10.1155/cjgh/6632867
Szabo, G., & Bala, S. (2013). MicroRNAs in liver disease. Nature Reviews Gastroenterology & Hepatology, 10(9), 542–552. https://doi.org/10.1038/nrgastro.2013.87
Tarantino, G., & Citro, V. (2024). Crosstalk between the spleen and other organs/systems: Downstream signaling events. Immuno, 4(4), 479–501. https://doi.org/10.3390/immuno4040030
Tarantino, G., Citro, V., Balsano, C., & Capone, D. (2021). Age and interleukin-15 levels are independently associated with intima-media thickness in obesity-related NAFLD patients. Frontiers in Medicine, 8, 634962. https://doi.org/10.3389/fmed.2021.634962
Thoma, M. V., La Marca, R., Brönnimann, R., Finkel, L., Ehlert, U., & Nater, U. M. (2013). The effect of music on the human stress response. PLoS ONE, 8(8), e70156. https://doi.org/10.1371/journal.pone.0070156
Thoma, M. V., Ryf, S., Mohiyeddini, C., Ehlert, U., & Nater, U. M. (2012). Emotion regulation through listening to music in everyday situations. Cognition and Emotion, 26(3), 550–560. https://doi.org/10.1080/02699931.2011.595390
Tracey, K. J. (2009). Reflex control of immunity. Nature Reviews Immunology, 9(6), 418–428. https://doi.org/10.1038/nri2566
Turecki, G., & Meaney, M. J. (2016). Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review. Biological Psychiatry, 79(2), 87–96. https://doi.org/10.1016/j.biopsych.2014.11.022
Ulrich-Lai, Y. M., & Herman, J. P. (2009). Neural regulation of endocrine and autonomic stress responses. Nature Reviews Neuroscience, 10(6), 397–409. https://doi.org/10.1038/nrn2647
Valadi, H., Ekström, K., Bossios, A., Sjöstrand, M., Lee, J. J., & Lötvall, J. O. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology, 9(6), 654–659. https://doi.org/10.1038/ncb1596
Vickers, K. C., Palmisano, B. T., Shoucri, B. M., Shamburek, R. D., & Remaley, A. T. (2011). MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nature Cell Biology, 13(4), 423–433. https://doi.org/10.1038/ncb2210
Vickhoff, B., Malmgren, H., Aström, R., Nyberg, G., Ekström, S. R., Engwall, M., Snygg, J., Nilsson, M., & Jörnsten, R. (2013). Music structure determines heart rate variability of singers. Frontiers in Psychology, 4, 334. https://doi.org/10.3389/fpsyg.2013.00334
Wang, H., Wang, Y., Chai, Y., Zhang, H., Chang, Q., Li, J., Zhang, R., & Bao, J. (2024). Prolonged exposure to a music-enriched environment mitigates acute noise-induced inflammation and apoptosis in the chicken spleen by modulating the Keap-1/Nrf2 and NF-κB pathways. Poultry Science, 103(10), 104100. https://doi.org/10.1016/j.psj.2024.104100
Woodburn, S. C., Asrat, H. S., Flurer, J. K., Schwierling, H. C., Bollinger, J. L., Vollmer, L. L., & Wohleb, E. S. (2023). Depletion of microglial BDNF increases susceptibility to the behavioral and synaptic effects of chronic unpredictable stress. Brain, Behavior, and Immunity, 109, 127–138. https://doi.org/10.1016/j.bbi.2023.01.014
Youssef, N. A., Abdelmalek, M. F., Binks, M., Guy, C. D., Omenetti, A., Smith, A. D., Diehl, A. M., & Suzuki, A. (2013). Associations of depression, anxiety and antidepressants with histological severity of nonalcoholic fatty liver disease. Liver International, 33(7), 1062–1070. https://doi.org/10.1111/liv.12165
Zaatar, M. T., Alhakim, K., Enayeh, M., & Tamer, R. (2023). The transformative power of music: Insights into neuroplasticity, health, and disease. Brain, Behavior, & Immunity - Health, 35, 100716. https://doi.org/10.1016/j.bbih.2023.100716
Zatorre, R. J., & Salimpoor, V. N. (2013). From perception to pleasure: Music and its neural substrates. Proceedings of the National Academy of Sciences of the United States of America, 110(Suppl. 2), 10430–10437. https://doi.org/10.1073/pnas.1301228110

Details

Primary Language

English

Subjects

Dentistry (Other)

Journal Section

Review

Authors

Giovanni Tarantino ^*
0000-0002-4014-5824
Italy

Early Pub Date

August 10, 2026

Publication Date

-

Submission Date

June 14, 2026

Acceptance Date

July 11, 2026

Published in Issue

Year 2026 Number: Advanced Online Publication

DOI

https://doi.org/10.62425/rtpharma.1969941

IZ

https://izlik.org/JA96AE49FB

Cite

RIS / Bibtex

APA

Tarantino, G. (2026). Therapeutic Music as a Neuroimmune–Metabolic Modulator in NAFLD: A Spleen‑Centered Working Hypothesis. Recent Trends in Pharmacology, Advanced Online Publication. https://doi.org/10.62425/rtpharma.1969941

AMA

1.Tarantino G. Therapeutic Music as a Neuroimmune–Metabolic Modulator in NAFLD: A Spleen‑Centered Working Hypothesis. Recent Trends in Pharmacology. 2026;(Advanced Online Publication). doi:10.62425/rtpharma.1969941

Chicago

Tarantino, Giovanni. 2026. “Therapeutic Music As a Neuroimmune–Metabolic Modulator in NAFLD: A Spleen‑Centered Working Hypothesis”. Recent Trends in Pharmacology, no. Advanced Online Publication. https://doi.org/10.62425/rtpharma.1969941.

EndNote

Tarantino G (August 1, 2026) Therapeutic Music as a Neuroimmune–Metabolic Modulator in NAFLD: A Spleen‑Centered Working Hypothesis. Recent Trends in Pharmacology Advanced Online Publication

IEEE

[1]G. Tarantino, “Therapeutic Music as a Neuroimmune–Metabolic Modulator in NAFLD: A Spleen‑Centered Working Hypothesis”, Recent Trends in Pharmacology, no. Advanced Online Publication, Aug. 2026, doi: 10.62425/rtpharma.1969941.

ISNAD

Tarantino, Giovanni. “Therapeutic Music As a Neuroimmune–Metabolic Modulator in NAFLD: A Spleen‑Centered Working Hypothesis”. Recent Trends in Pharmacology. Advanced Online Publication (August 1, 2026). https://doi.org/10.62425/rtpharma.1969941.

JAMA

1.Tarantino G. Therapeutic Music as a Neuroimmune–Metabolic Modulator in NAFLD: A Spleen‑Centered Working Hypothesis. Recent Trends in Pharmacology. 2026. doi:10.62425/rtpharma.1969941.

MLA

Tarantino, Giovanni. “Therapeutic Music As a Neuroimmune–Metabolic Modulator in NAFLD: A Spleen‑Centered Working Hypothesis”. Recent Trends in Pharmacology, no. Advanced Online Publication, Aug. 2026, doi:10.62425/rtpharma.1969941.

Vancouver

1.Giovanni Tarantino. Therapeutic Music as a Neuroimmune–Metabolic Modulator in NAFLD: A Spleen‑Centered Working Hypothesis. Recent Trends in Pharmacology. 2026 Aug. 1;(Advanced Online Publication). doi:10.62425/rtpharma.1969941