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

The DOI matches its Crossref record; 226 of the 226 references it cites were found in a registry or an index.

Immunopathogenic mechanisms and immunoregulatory therapies in MASLD

Open access
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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Crossref · 10.1038/s41423-025-01307-5

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Figures

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 conversion
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 progression
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 MASLD
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 MASLD
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 response
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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Metadata

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
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
Licence
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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