The bidirectional immune crosstalk in metabolic dysfunction-associated steatotic liver disease
Open accessAbstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an unabated risk factor for end-stage liver diseases with no available therapies. Dysregulated immune responses are critical culprits of MASLD pathogenesis. Independent contributions from either the innate or adaptive arms of the immune system or their unidirectional interplay are commonly studied in MASLD. However, the bidirectional communication between innate and adaptive immune systems and its impact on MASLD remain insufficiently understood. Given that both innate and adaptive immune cells are indispensable for the development and progression of inflammation in MASLD, elucidating pathogenic contributions stemming from the bidirectional interplay between these two arms holds potential for development of novel therapeutics for MASLD. Here, we review the immune cell types and bidirectional pathways that influence the pathogenesis of MASLD and highlight potential pharmacologic approaches to combat MASLD based on current knowledge of this bidirectional crosstalk.
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The roles of Tregs in MASLD and MASH remain unclear, with hepatic accumulation and functional relevance varying depending on the disease model.
“The roles of Tregs in MASLD and MASH remain unclear, with emerging evidence suggesting that their hepatic accumulation and functional relevance may vary depending on the disease model employed (Sawada et al. 2023).”
From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Sawada et al. 2023
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“In fi ltration and activation of immune cells may activate the innate and adaptive immune systems by secreting in fl ammatory cytokines, which in turn drive the development and progression of MASLD (9).”
Autoantibodies are associated with worse outcomes in MASLD
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“47 A recent study demonstrated that the absence of speci fi c B-cell populations or impaired antibody secretion (IgMi mice) protects against hepatic steatosis, in fl ammation, and fi brosis in an MASLD mouse model.”
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Licochalcone D ameliorates lipid metabolism in hepatocytes by modulating lipogenesis and autophagy.
Liou, C.-J., Wu, S.-J., Yang, H., Fang, L.-W., Cheng, S.-C., & Huang, W.-C. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.176644 · Cited by 6
Luo, Z.-G., Yan, S., Chao, Y.-H., & Shen, M. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e28935 · Cited by 6 · see citing works
“…cell recruitment in NAFLD, can secrete large amounts of quantities of IL-6 and proteases, including myeloperoxidase, neutrophil elastase, and protease 3, enhancing the inflammatory environment, promoting ROS, and causing hepatocyte damage, thus contributing to the progression of NASLD[60 – 64].”
BackgroundLi, Y. C., Hu, Y., He, Y. M., Yang, Y., Xue, D., Xue, E., Jia, J., Zhang, W., & Wang, J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1793092 · Cited by 4 · see citing works
“Overall, coordinated alterations in multiple metabolic signals may collectively reprogram the metabolic state of hepatic immune cells, favoring the maintenance of pro-in fl ammatory metabolic programs while reducing sensitivity to inhibitory regulatory cues (14, 50).”
Circulating histones as potential biomarkers of MASLD-MASH-HCC progression.
Tsoneva, D. K., Buzova, D., Bianco, S., Braghini, M. R., Andolina, G., Liguori, A., D'Ambrosio, F., Urbani, A., Gasbarrini, A., Pompili, M., et al. (2026) · Epigenomics · doi:10.1080/17501911.2025.2611415 · Cited by 5 · see citing works
Jia, L.-Y., Bai, X., Ni, W.-J., Yin, S.-X., Shi, J.-P., Yang, Y.-F., & Li, J. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115553 · Cited by 5 · see citing works
Bai, Y., Ju, J.-Y., Xie, R., Li, J., Zhao, X.-Y., Fang, X., Zhu, M., Lan, X., & Luo, H.-M. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115539 · Cited by 5 · see citing works
Engineering microfluidic human liver-islet crosstalk platform for recapitulating MASLD
Li, J., Wu, Z., Gan, J., Zhi, Y., Zhao, Y., & Li, L. (2025) · Chemical Engineering Journal · doi:10.1016/j.cej.2025.165209 · Cited by 3 · see citing works
Yang, L., Li, W., Chen, Y., Ya, R., Qian, S., Liu, L., Hao, Y., Zai, Q., Xiao, P., Hwang, S., et al. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.06.007 · Cited by 3 · see citing works
“Similarly, in pediatric patients with MASLD diagnosed by biopsy, approximately 50% of patients develop MASH, and 16% — 31% have advanced fibrosis 5,6 .”
Arai, J., Okumura, A., Kimoto, S., Sakamoto, K., Kitada, T., Kitano, R., Inoue, T., Nishimura, S., Inden, N., Muraki, Y., et al. (2025) · Hepatology International · doi:10.1007/s12072-025-10800-y · Cited by 3 · see citing works
“Notably, studies on immune responses in MASLD have traditionally focused on the role of innate immunity in disease development and progression [23].”
Ünal, K., Ibrahimkhanlı, L., Erol, M. E., Ibrahimkhanli, N., Altıntop, S. E., Cerit, M. N., Cerit, E. T., & Şendur, H. N. (2026) · International Journal of Tryptophan Research · doi:10.1177/11786469261423510 · Cited by 4 · see citing works
“2-4 The pathogenesis of MASLD is now primarily explained by the “multiple-hit” hypothesis, 5 which involves factors such as insulin resistance, hormones secreted by adipose tissue, nutritional factors, gut microbiota, and genetic factors.”
Gjurašin, B., Matotek, L. R., Marković, L. Š., & Papić, N. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26168095 · Cited by 4 · see citing works
“Prior human studies in MASLD have shown increased baseline IL-6, IL-17A and TGF-β 1 which are associated with hepatic inflammation, insulin resistance, and fibrosis [26,27].”
Multifaceted Human Antigen R (HuR): A Key Player in Liver Metabolism and MASLD
Eppler, N., Jones, E., Ahamed, F., & Zhang, Y. (2025) · Livers · doi:10.3390/livers5030033 · Cited by 3 · see citing works
“These livers show increased infiltration of NKT cells and CD8 + T cells, immune subsets commonly associated with severe inflammation and fibrosis in MASLD [101,202,203].”
InfluentialSex-Dependent T Cell Dysregulation in Mice with Diet-Induced Obesity
Brummer, C., Singer, K., Brand, A., Bruss, C., Renner, K., Herr, W., Pukrop, T., Dorn, C., Hellerbrand, C., Matos, C., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25158234 · Cited by 4 · see citing works
X-chromosome gene dosage shapes MASLD beyond sex hormones
Jamalinia, M., Targher, G., & Lonardo, A. (2026) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2026.05.001 · Cited by 3 · see citing works
Liu, L., Duan, X., & Ju, B.-Z. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2025.1744299 · Cited by 3 · see citing works
Ye, B.-C., Teng, Y., Chen, Q.-Q., Zhang, J., Li, S., Dong, L., Xu, C., Qiao, X., & Miao, X. (2025) · npj Digital Medicine · doi:10.1038/s41746-025-02220-x · Cited by 3 · see citing works
Lu, Y., Liu, L., Zhou, M., Zou, M., Ju, L., Yao, D., & Yao, M. (2025) · Liver International · doi:10.1111/liv.70421 · Cited by 2 · see citing works
“…from both HFD and HCC groups exhibited significant upregulation of immune system processes and leukocyte activation pathways, with prominent enrichment in lymphocyte activation modules, indicating a state of heightened immune activation dominated by lymphocytes in the MASLD environment [22, 23].”
Tram, V. T. N., Xuan, D. T. M., Nguyen, D. P. Q., Anuraga, G., & Ta, H. D. K. (2025) · Comput. Biol. Medicine · doi:10.1016/j.compbiomed.2025.110653 · Cited by 3
Vizioli, G., Nicoletti, A., Daniela, F., Funaro, B., Verme, L. Z. D., Ponziani, F. R., Zocco, M. A., Gasbarrini, A., & Gabrielli, M. (2025) · Applied Sciences · doi:10.3390/app15052279 · Cited by 1 · see citing works
Onisor, D., Roiban, A. L., & Cernea, S. (2024) · Medicina · doi:10.3390/medicina60122091 · Cited by 3 · see citing works
Lee, S. E., Jo, M. G., Park, S. W., Kim, H. J., Yun, S. P., & Kim, J.-W. (2026) · Animal Cells and Systems · doi:10.1080/19768354.2026.2630463 · Cited by 2 · see citing works
“The roles of Tregs in MASLD and MASH remain unclear, with emerging evidence suggesting that their hepatic accumulation and functional relevance may vary depending on the disease model employed (Sawada et al. 2023).”
Li, S., Lambertucci, F., Montégut, L., Martins, I., Pol, J. G., Piacentini, M., Maiuri, M. C., & Kroemer, G. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-08148-0 · Cited by 3 · see citing works
“Its decisions ripple outward, in fl uencing the behavior of virtually every organ — dictating energy supply, affecting nutrient absorption, calibrating biosynthesis, orchestrating detoxi fi cation, and modulating immune activity [3, 4].”
Pan-immune-inflammation value and mortality in the US adult MASLD: a nonlinear NHANES analysis
Zhou, Q., Xue, J., & Hao, L. (2025) · BMC Gastroenterology · doi:10.1186/s12876-025-04064-x · Cited by 2 · see citing works
Jin, Z., Cao, J., Liu, Z.-X., Gao, M., & Liu, H.-L. (2025) · Metabolism Open · doi:10.1016/j.metop.2025.100366 · Cited by 2 · see citing works
“Hepatic immune cell populations reshape during MASH and contribute to disease pathogenesis [1].”
InfluentialYe, D., Wang, J., Shi, J., Ma, Y., Chen, J., Hu, X., & Bao, Z. (2024) · Lipids in Health and Disease · doi:10.1186/s12944-024-02245-3 · Cited by 2 · see citing works
“Recent investigations have highlighted the role of immune mediators from both resident liver parenchymal cells and a cohort of resident and infiltrating immune cells in precipitating the activation of innate and adaptive immune responses, thereby promoting the onset and progression of MASLD [30].”
BackgroundSawada, K., Oates, J. R., Kimura, M., Stankiewicz, T. E., Eom, J., Alarcon, P. C., Chung, H., Damen, M. S. M. A., Ulanowicz, C. J., Wayland, J. L., et al. (2026) · Cell Metabolism · doi:10.1016/j.cmet.2026.08.018
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Vecchio, C., Sheferaw, A. N., Kivumbi, E., Stoppa, I., Pantham, D., Christaki, F., Provera, A., Dianzani, U., & Sutti, S. (2026) · Inflammation · doi:10.1007/s10753-026-02545-z · Cited by 1 · see citing works
“…stages of disease, these cells may exert regulatory functions, whereas in more advanced stages, they acquire a pro-inflammatory and pro-fibrotic phenotype, releasing cytokines and chemokines that promote the recruitment of neutrophils and macrophages and activate hepatic stellate cells [161–163].”
Chng, W., Liew, J., Liew, C., Muthiah, M., Zheng, M.-H., & Oon, H. H. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1831174 · Cited by 1 · see citing works
“In psoriasis, Th17 cells are activated by the IL-23 pathway through myeloid dendritic cells 10 .”
InfluentialYou, X., Zhang, L., Fang, K., Huang, H.-F., Hu, Y., Gu, M., Qu, Q., Xue, F., Huang, S.-X., Wu, Z., et al. (2026) · Genes & Diseases · doi:10.1016/j.gendis.2026.102297 · Cited by 1 · see citing works
Boateng, S., Nguefang, G., Mapouka, M., Lawal, R., Gyabaah, S., Nwatamole, B., Kasar, A., Adatsi, S., & Njei, B. (2026) · Gastro Hep Advances · doi:10.1016/j.gastha.2026.101030 · Cited by 1 · see citing works
Effects and Mechanisms of Stevioside on Metabolic Dysfunction‐Associated Steatotic Liver Disease
Li, K., Zhang, C., Kang, L., Mu, Y., Li, Z., Zhang, J. I.-X., & Li, G. H. (2026) · Food Science & Nutrition · doi:10.1002/fsn3.71945 · Cited by 1 · see citing works
Ambient temperature regulates CD4+ T cell tonic T cell receptor signaling and responsiveness
Sawada, K., Eom, J., Mahoney-Sutherland, B. A., Stankiewicz, T. E., Oates, J. R., Giles, D. A., Alarcon, P. C., Damen, M. S. M. A., Cannata, A., Hargis, J., et al. (2026) · iScience · doi:10.1016/j.isci.2026.115801 · Cited by 2 · see citing works
“To interrogate this relationship in MASLD, WT mice were fed a high-fat diet for 20 weeks in either Tn-or Ts-conditions (Figure 5A).”
InfluentialSelf-citationRomeo, M., Basile, C., Martinelli, G., Nardo, F. D., Napolitano, C., Gregorio, A. D., Vaia, P., Puorto, L. D., Indipendente, M., Federico, A., et al. (2026) · Cancers · doi:10.3390/cancers18081316 · Cited by 1 · see citing works
Nash, M. J., Nelson, B. N., McGuckin, M., Janssen, R., Jones, K. L., Al-Juboori, S. I., Dobrinskikh, E., Kievit, P., Aagaard, K., McCurdy, C. E., et al. (2026) · bioRxiv · doi:10.64898/2026.01.06.697995 · Cited by 1 · see citing works
“Macrophage activation promotes MASLD progression in adults 34 .”
MASLD: Lipotoxicity and Imaging Parallels from Liver Steatosis to Kidney Injury
Săndulescu, S. M., Ghiga, D. Ș., Tudoraşcu, D. R., Săndulescu, L., Mită, A., Urhuț, M. C., & Taisescu, C. I. (2025) · Life · doi:10.3390/life15121805 · Cited by 3 · see citing works
“Beyond the innate cascade detailed above, adaptive immunity through dendritic cells, natural killer cells, and T and B lymphocytes also contributes, and its bidirectional crosstalk with innate immunity in MASLD has been recently reviewed [65].”
Lee, J.-D., Kwak, J., Kim, M.-H., Lee, S.-H., Cho, J.-H., Lim, D.-J., Lee, J.-M., Chang, S.-A., & Kim, H. (2025) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.2025.006 · Cited by 1 · see citing works
“The hypothesized association between MASLD and thyroid cancer could be mediated through mechanisms such as chronic inflammation, insulin resistance, and altered adipokine levels, which are key features of metabolic dysfunction [8].”
Zhang, F., Liu, L.-G., & Li, W.-J. (2025) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-025-01724-6 · Cited by 1
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“8,9 Hepatic immune cells exhibit diversity in the steady state and continue to evolve during NASH, directly impacting the disease’s severity.”
Ren, M., Ren, J., Zheng, J., Sha, X.-T., Lin, Y., & Wu, F.-H. (2024) · Antioxidants · doi:10.3390/antiox13091136 · Cited by 1
“Fatty liver patients with obesity, overweight, insulin resistance, dyslipidemia, and other metabolic factors can be diagnosed as MASLD [1].”
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Glutamine metabolism keeps pathogenic hepatic CD4+ T cells in check.
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Onoiu, A.-I., González-Serrano, S., Cambra-Cortés, V., Jiménez-Franco, A., Guilarte, C., Peña, K. B., Riu, F., Camps, J., Joven, J., & Parada, D. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1816648
Cyclo(Val-Pro) and cyclo(Phe-Phe) alleviate MASLD via distinct CCR2- and ADCY7-associated pathways.
Zhou, J., Jin, H.-J., Zheng, Y.-F., Ding, K.-Y., Long, Y., Yu, C.-J., Zhang, Y.-R., Zhuge, F., Chen, M.-H., Fu, Z.-W., et al. (2026) · Life Science · doi:10.1016/j.lfs.2026.124669
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- Authors
- Sawada, K., Chung, H., Softic, S., Moreno-Fernandez, M. E., & Divanovic, S.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- University of Kentucky (US)
- Corresponding author
- Divanovic, Senad
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2023-11
- Volume
- 35
- Issue
- 11
- Pages
- 1852-1871
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC10680147
- OpenAlex
- W4388452323
- Cited by
- 139
- References
- 316
- Citations by year
- 2026: 56 · 2025: 51 · 2024: 32
- FWCI
- 5.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association (17POST33650045)
- CCHMC
- Cincinnati Children’s Research Foundation
- National Institutes of Health (R01DK099222)
- U.S. Department of Defense (W81XWH2010392)
- American Diabetes Association (1-18-IBS-100)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- non-alcoholic fatty liver disease, innate immunity, adaptive immunity, liver inflammation, immune cell types, therapeutic target
- MeSH terms
- Fatty Liver, Humans, Inflammation, Metabolic Diseases, Pancreas, Risk Factors
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