Cited by 81Liver Disease Diagnosis and TreatmentLiver physiology and pathologyLiver Diseases and Immunity

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Immunopathogenic mechanisms and immunoregulatory therapies in MASLD

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He, Yong, Chen, Yingfen, Qian, Shengying, van Der Merwe, Schalk, Dhar, Debanjan, Brenner, David A., Tacke, Frank·2025·Cellular & Molecular Immunology

DOI 10.1038/s41423-025-01307-5PMC PMC12480724

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), is the most prevalent chronic liver disease worldwide, with an estimated global prevalence of approximately 30%; however, effective pharmacotherapies are still limited due to its complex pathogenesis and etiology. Therefore, a more thorough understanding of disease pathogenesis is urgently needed. An increasing number of studies suggest that MASLD and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are driven by chronic overnutrition, multiple genetic susceptibility factors, and pathogenic consequences, including hepatocyte damage and liver inflammation. Hepatic inflammation is the key event fueling the conversion from simple steatosis to steatohepatitis and fibrosis. Current therapies for MASH, including the recently approved thyroid hormone receptor-beta agonist resmetirom or the available incretin mimetics, mainly target metabolic injury to the liver but not inflammation directly. In this review, we provide an in-depth discussion of current data related to the immunological mechanisms of MASLD and summarize the effects of current and experimental therapies on immunoregulation in MASLD.

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Fig. 1 A spectrum of MASLD. MASLD represents a spectrum of disorders ranging from simple steatosis to MASH, ultimately resulting in advanced fibrosis, cirrhosis and cancer. Immunological mechanisms are involved in the development of MASLD, especially simple steatosis-to-MASH conversionCC BY · PubMed Central

Fig. 2 Major subtypes of liver macrophages based on their transcriptomic signature in MASLD. Liver macrophages include resident Kupffer cells (EmKCs) and monocyte-derived macrophages (MdMs). MdMs can infiltrate the liver and can be further classified into different MASH-associated macrophage subsets, which play critical roles in MASLD development and progressionCC BY · PubMed Central

Fig. 3 The diverse roles of different immune cells in MASLD. Two subsets of EmKCs are identified in MASLD, including a major CD206loESAM- population (KC1) and a minor CD206hiESAM+ population (KC2), which have specific transcriptomic and proteomic signatures. Neutrophil-derived NETs exacerbate MASH-related liver fibrosis by inducing metabolic reprogramming of HSCs. NETs accelerate alcohol-induced acceleration of MASH-related liver fibrosis by activating HSCs and monocytes via NLRP3. Lymphocytes, including T cells, B cells, and innate lymphoid cells, play critical and diverse roles in MASLDCC BY · PubMed Central

Fig. 4 Other immunological mechanisms of MASLD. Metabolic reprogramming, epigenetic regulation and inflammatory signaling pathways in immune cells play essential roles in the pathogenesis of MASLDCC BY · PubMed Central

Fig. 5 Immunoregulatory therapies for MASLD. Although most pharmacological strategies primarily target metabolic processes, aiming at ameliorating metabolic dysfunction-driven stress and injury in hepatocytes, these potential “MASH therapies” also inhibit the immune cell-mediated inflammatory responseCC BY · PubMed Central

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Items 201–226 of 226

Hepatocyte CHRNA4 mediates the MASH-promotive effects of immune cell-produced acetylcholine and smoking exposure in mice and humans
Pan, C., Liu, J., Gao, Y., Yang, M., Hu, H., Liu, C., Qian, M., Yuan, H.-Y., Yang, S., Zheng, M.-H., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.10.018 · Cited by 27 · cited 2×
“Notably, CHRNA4 inhibition by lobeline prevents acetylcholine binding, thereby reducing immune cell recruitment and mitigating MASH progression [143].”
Two years on, a perspective on MAFLD
Eslam, M., & George, J. (2023) · eGastroenterology · doi:10.1136/egastro-2023-100019 · Cited by 26 · cited 2×
“Therefore, an international panel of experts has detailed the rationale for an update of the nomenclature, and metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed as a more appropriate term to describe this liver disease [4 – 6].”
Monocyte bioenergetics: An immunometabolic perspective in metabolic dysfunction-associated steatohepatitis
Sangineto, M., Ciarnelli, M., Colangelo, T., Moola, A., Bukke, V. N., Duda, L., Villani, R., Romano, A. D., Giandomenico, S., Kanwal, H., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101564 · Cited by 26 · cited 1×
“A recent study revealed a distinct bioenergetic phenotype in the circulating monocytes of mouse MASH models and patients with MASH, characterized by the upregulation of the mitochondrial and glycolytic energy pathways [103].”
Washed microbiota transplantation promotes homing of group 3 innate lymphoid cells to the liver via the CXCL16/CXCR6 axis: a potential treatment for metabolic-associated fatty liver disease
Zhong, H., Zhuang, Y.-P., Xie, X., Song, J., Wang, S., Wu, L., Zhan, Y., Wu, Q., & He, X. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2372881 · Cited by 25
Naringenin cationic lipid-modified nanoparticles mitigate MASLD progression by modulating lipid homeostasis and gut microbiota
Dong, L., Lou, W., Xu, C., & Wang, J. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03228-x · Cited by 25 · cited 1×
“…addition, naringenin cationic lipid-modi ﬁ ed nanoparticles (NP-NAR) have been reported to alleviate MASLD progression by promoting fatty acid oxidation and modulating the gut microbiota, leading to the amelioration of lipid dysbiosis, oxidative stress, insulin resistance, and in ﬂ ammation [168].”
Microbiota-derived H2S induces c-kit+ cDC1 autophagic cell death and liver inflammation in metabolic dysfunction-associated steatohepatitis
Song, Y., Li, N., Jiang, S., Wang, K., Lv, G., Fan, Z., Du, X., Gao, W., Lei, L., Wang, Z., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57574-3 · Cited by 25
Gut inflammation exacerbates high-fat diet induced steatosis by suppressing VLDL-TG secretion through HNF4α pathway
Li, P., Chen, X., Dong, M., Luo, J. F., Lu, S., Chen, M., Zhang, Y., Zhou, H., & Jiang, H. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.06.027 · Cited by 24
Sonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic steatohepatitis in mice
Zhang, W., Lu, J., Feng, L., Xue, H., Shen, S., Lai, S., Li, P., Li, P., Kuang, J., Yang, Z., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45520-8 · Cited by 22 · cited 1×
“For example, miR-28-5p secreted by hepatocytes stimulates the expression of in ﬂ ammatory factors in macrophages to aggravate MASH [121].”
The Nr4a family regulates intrahepatic Treg proliferation and liver fibrosis in MASLD models
Aki, D., Hayakawa, T., Srirat, T., Shichino, S., Ito, M., Saitoh, S.-I., Mise-Omata, S., & Yoshimura, A. (2024) · Journal of Clinical Investigation · doi:10.1172/jci175305 · Cited by 22 · cited 1×
“Another study demonstrated that a massive accumulation of Tregs in the livers of MASH mice ameliorated liver cell death and ﬁ brosis, thus mitigating liver dysfunction in MASH [77].”
MicroRNAs in metabolic dysfunction‐associated diseases: Pathogenesis and therapeutic opportunities
Ma, N., Tan, J., Chen, Y., Liu, Y., Li, M., & He, Y. (2024) · The FASEB Journal · doi:10.1096/fj.202401464r · Cited by 21 · cited 1×
“Moreover, the functions of noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs), have been widely studied in MASLD [113, 114].”
Self-citation
New therapeutic target for alcohol-associated hepatitis (AH): AH-associated IL-8+ neutrophils
Guan, Y., Feng, D., Maccioni, L., Wang, Y., & Gao, B. (2024) · eGastroenterology · doi:10.1136/egastro-2024-100166 · Cited by 21 · cited 1×
“However, neutrophils are the most abundant leukocyte type in the human circulation [219], and neutrophil in ﬁ ltration is commonly observed in human MASH, as well as in alcohol-related SLD [220, 221].”
Free Fatty Acid Receptors (FFARs): Emerging Therapeutic Targets for the Management of Diabetes Mellitus
Loona, D. P. S., Das, B., Kaur, R., Kumar, R., & Yadav, A. K. (2022) · Current Medicinal Chemistry · doi:10.2174/0929867329666220927113614 · Cited by 20
Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells
Xie, Y., Huang, Y., Li, Z.-Y., Jiang, W., Shi, N.-X., Lu, Y., Cao, G., Yin, Z., & Lin, X.-J. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02001-2 · Cited by 18 · cited 1×
“IL-21R signaling has been shown to promote MASH-HCC via the induction of immunosuppressive IgA + B cells [23].”
Essential roles of B cell subsets in the progression of MASLD and HCC
Petriv, N., Suo, H., Hochnadel, I., Timrott, K., Bondarenko, N., Neubert, L., Reinhard, E., Jedicke, N., Kaufhold, P., Guzmán, C. A., et al. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2024.101189 · Cited by 17 · cited 1×
“B cells [85].”
Myeloid-specific ablation of Basp1 ameliorates diet-induced NASH in mice by attenuating pro-inflammatory signaling
Meng, Z., Zhou, L., Hong, S., Qiu, X., Chen, Z., Liu, T., Inoki, K., & Lin, J. D. (2023) · Hepatology · doi:10.1097/hep.0000000000000537 · Cited by 16
E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction‐Associated Steatohepatitis
Liu, Z., Wang, H., Liang, Y., Liu, M., Huang, Q., Wang, M., Zhou, J., Bu, Q., Zhou, H., & Lü, L. (2024) · Advanced Science · doi:10.1002/advs.202410880 · Cited by 16 · cited 1×
“A mechanistic study further revealed that E2f2 deletion in macrophages fueled proin ﬂ ammatory responses in a Leu-mTORC1-dependent manner by enhancing glycolysis and impairing mitochondrial function by increasing SLC7A5 expression [105].”
Compromised macrophages contribute to progression of MASH to hepatocellular carcinoma in FGF21KO mice
Shi, X., Zheng, Q., Wang, X., Guo, W., Lin, Z., Gao, Y., Shore, E. A., Martin, R. C. G., Lv, G., & Li, Y. (2024) · Science Advances · doi:10.1126/sciadv.ado9311 · Cited by 15 · cited 2×
“For example, ﬁ broblast growth factor 21 (FGF21) exhibits important anti-in ﬂ ammatory activity, and its de ﬁ ciency can induce excessive KC death and accelerate the MASH-HCC transition [22].”
PPARα suppresses growth of hepatocellular carcinoma in a high-fat diet context by reducing neutrophil extracellular trap release
Pan, B., Zhang, Z., Ye, D., Zhang, X., Yao, Y., Luo, Y., Hong, H., Cai, X., Chen, Y., & Tang, N. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2024.101228 · Cited by 14 · cited 1×
“In addition, NETs are able to promote the differentiation of regulatory T cells (Tregs), which contribute to carcinogenesis in MASLD [76], whereas activating PPAR α can reduce NET formation in a high-fat diet (HFD) context [111].”
Self-citation
Steatotic liver disease: a new name to reflect the combined role of alcohol and metabolic dysfunction
Krag, A. A., & Rinella, M. E. (2024) · Nature Medicine · doi:10.1038/s41591-024-02849-3 · Cited by 12 · cited 1×
“Of particular importance is the new category of individuals with MetALD, whose diagnosis of hepatic steatosis requires the presence of cardiometabolic risk factors (CMRFs) and daily alcohol intake between 20 – 50 g/day for women and between 30 – 60 g/day for men [11, 12].”
Genome‐Wide Profiling of H3K27ac Identifies TDO2 as a Pivotal Therapeutic Target in Metabolic Associated Steatohepatitis Liver Disease
Zhu, Y., Shang, L., Tang, Y., Li, Q., Ding, L., Wang, Y., Zhang, T., Xie, B., Ma, J., Li, X., et al. (2024) · Advanced Science · doi:10.1002/advs.202404224 · Cited by 11 · cited 1×
“Genome-wide pro ﬁ ling of the acetylation of histone H3 lysine 27 (H3K27ac), a marker of active enhancers and promoters, revealed that H3K27ac density is signi ﬁ cantly altered in the livers of MASLD rats, along with abundant alterations in the regulatory transcriptome [109].”
Molecular imaging of macrophage composition and dynamics in MASLD
Yang, B. Q., Chan, M. M., Heo, G. S., Lou, L., Luehmann, H. P., Park, C., Li, A., Lahad, D., Sultan, D. H., Voller, P., et al. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2024.101220 · Cited by 11 · cited 1×
“To visualize these cells and processes, positron emission tomography (PET) imaging of recruited macrophages by targeting CCR2 and CD163 has translational potential for the diagnosis and monitoring of MASH [58].”
Inflammation in Steatotic Liver Diseases: Pathogenesis and Therapeutic Targets
Qian, S., Wang, X., Chen, Y., Zai, Q., & He, Y. (2024) · Seminars in Liver Disease · doi:10.1055/a-2338-9261 · Cited by 6
Self-citation
Resmetirom: Breakthrough therapeutic approach for metabolic dysfunction-associated steatohepatitis
Saeed, A., Rai, K. D., & Saeed, M. (2024) · Liver Research · doi:10.1016/j.livres.2024.07.002 · Cited by 5 · cited 1×
“Although the ﬁ rst pharmacotherapeutic for MASLD and MASH, resmetirom, has been approved for clinical use [224], we expect more targeted treatments owing to the modest ef ﬁ cacy of resmethrin [2].”
Macrophage Notch1 signaling modulates regulatory T cells via the TGFB axis in early MASLD
Zhang, M., Li, K., Huang, X., Xu, D., Zong, R., Hu, Q., Dong, X., Zhang, Q., Jiang, C., Ge, Y., et al. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2024.101242 · Cited by 5 · cited 3×
“Nevertheless, the number of Tregs was found to be decreased in early MASLD, contributing to high-fat diet-induced hepatic steatosis [78].”
Influential
Generative AI: A transformative force in advancing research and care in metabolic dysfunction-associated fatty liver disease
Ray, P. P. (2024) · Liver Research · doi:10.1016/j.livres.2024.05.002 · Cited by 3 · cited 1×
“…opportunity to advance our understanding and management of MASLD, such as tabular medical data analysis, multiomics data analysis, the generation of synthetic patient data, enhancing the medical imaging ﬁ eld for MASLD, and advancing personalized medicine approaches for MASLD [216, 217].”
Role of Neutrophils in the Development of Steatotic Liver Disease
Choi, Y., Kim, Y. S., & Hwang, S. (2024) · Seminars in Liver Disease · doi:10.1055/s-0044-1789207 · Cited by 2 · cited 1×
“The role of neutrophils has garnered attention for their involvement in sterile in ﬂ ammation, which plays a pivotal role in the pathogenesis of steatotic liver disease [66].”

Sorted by citations

Metabolic dysfunction and alcohol-associated liver disease (MetALD)
Gao, B., Arab, J. P., Liangpunsakul, S., Ding, W., Szabó, G., Mehal, W. Z., Wang, H., He, Y., Stärkel, P., Llorente, C., et al. (2025) · eGastroenterology · doi:10.1136/egastro-2025-100319 · Cited by 43
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High systemic inflammation response index and increased cardiovascular risk and mortality in MASLD: A prospective cohort study
Zheng, H., Wu, K., Zheng, H., Chen, G., Lan, Y., Chen, S., Casu, G., Sechi, L. A., Wu, S., Vidili, G., et al. (2025) · JHEP Reports · doi:10.1016/j.jhepr.2025.101602 · Cited by 18
“…Neutrophil extracellular trap formation, M1 macrophages polarization, and T-cell imbalance contribute to hepatic inflammation and fibrosis, 38 while the same mechanisms also drive vascular inflammation, foam cell formation, and plaque instability, linking systemic immune activation to…”
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The many pathways driving liver inflammation in MASH
Tilg, H., Adolph, T. E., Romeo, S., & Loomba, R. S. (2026) · Cell Metabolism · doi:10.1016/j.cmet.2026.02.018 · Cited by 17
Primary Human Tissue Models for Metabolic Dysfunction‐Associated Liver Disease ‐ toward Streamlining Drug Discovery with Patient‐Derived Assays
Youhanna, S., Taebnia, N., Liang, Y., Cheng, N., Wang, Y., Michel, M., & Lauschke, V. M. (2025) · Advanced Biology · doi:10.1002/adbi.202500337 · Cited by 9
Associations Between Systemic Inflammatory Markers, Metabolic Dysfunction, and Liver Fibrosis Scores in Patients with MASLD
Eid, R. A., Hamed, A. M., Elgendy, S. O., Orayj, K. M., Ibrahim, A. S., Hamied, A. M. A., Wahsh, E. A., Youssif, M., Rabea, H., Madney, Y. M., et al. (2025) · Metabolites · doi:10.3390/metabo16010025 · Cited by 9

See all 81

Authors: He, Y., Chen, Y., Qian, S., van Der Merwe, S., Dhar, D., Brenner, D. A., & Tacke, F.
Affiliations: Chinese Academy of Sciences (CN)
Sanford Burnham Prebys Medical Discovery Institute (US)
Charité – Universitätsmedizin Berlin (DE)
Corresponding author: He, Yong
Tacke, Frank
ORCID: He, Yong
Chen, Yingfen
Qian, Shengying
Dhar, Debanjan
Brenner, David A.
Tacke, Frank
Venue: Cellular & Molecular Immunology
Publisher: Springer Science and Business Media LLC
Published: 2025-06-10
Volume: 22
Issue: 10
Pages: 1159-1177
ISSN: 1672-7681 (ISSN-L)
2042-0226
DOI: 10.1038/s41423-025-01307-5
PMC: PMC12480724
OpenAlex: W4411162672
Semantic Scholar: 7f2f36cf67705164236941f4c20e7acd81779cf2
Cited by: 81
References: 226
Citations by year: 2026: 63 · 2025: 18
FWCI: 12.44
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Cellular and Molecular Immunology (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed (publishedVersion)
PubMed Central (publishedVersion, cc-by)
Lirias (KU Leuven) (submittedVersion, cc-by)
Funders: U.S. Department of Health and Human Services (R01DK133930, RO1DK137061)
Deutsche Forschungsgemeinschaft (SFB 1382, DFGTa434/8‐1, Ta434/8‐1, 403224013)
National Natural Science Foundation of China (82270601, 403224013)
National Institutes of Health
National Key Research and Development Program of China (2024ZD0530604, 2023YFA1800804)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK137061, R01DK133930)
Topics: Health Sciences › Medicine › Hepatology › 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, nonalcoholic steatohepatitis, immunopathogenesis, liver inflammation, immunomodulatory therapy, resmetirom, incretin mimetics, liver fibrosis, genetic susceptibility, overnutrition
MeSH terms: Animals, Humans, Liver, Immunomodulation, Non-alcoholic Fatty Liver Disease

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