CD73 promotes the immunoregulatory functions of hepatic Tregs through enzymatic and nonenzymatic pathways in MASLD development
Open accessAbstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading chronic liver disease characterized by chronic inflammation. Regulatory T cells (Tregs) highly express CD73 and play a critical role in modulating the immune response. However, the roles and mechanisms by which CD73 modulates Tregs in MASLD are still unknown. A choline-deficient high-fat diet (CDHFD) or methionine/choline-deficient diet (MCD) was used to establish a MASLD model. We found that CD73 expression was upregulated in Tregs via the FFA-mediated p38/GATA2 signaling pathway. Cd73 KO promoted MASLD progression, accompanied by decreased Treg viability and activity. Compared with Cd73 KO Tregs, adoptively transferred WT Tregs exhibited increased Treg activity and provided greater protection against hepatic inflammatory responses in MASLD. This immune protection is mediated by CD73 via both enzymatic and nonenzymatic pathways, degrading AMP into ADO to increase Treg function and block DR5-TRAIL-mediated cell death signaling. These findings suggest a potential immunotherapeutic approach for MASLD treatment and highlight its possible relevance for clinical application. • MASLD upregulates CD73 expression in liver Tregs. • CD73 KO mice promote the progression of MASLD. • CD73 maintains Treg viability and immunoregulatory function in MASLD. • FFAs increase CD73 expression on Tregs via the p38/Gata2 signaling pathway. • CD73 promotes Treg survival and function via enzymatic/nonenzymatic pathways.
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Adoptive transfer of ex vivo-expanded Tregs can reduce intrahepatic TNF-α signaling, dampen hepatotoxic responses to LPS, and alleviate hepatic inflammation in MASLD models.
“Several studies have shown that adoptive Treg transfer can reduce intrahepatic TNF-α signaling, dampen hepatotoxic responses to LPS, and alleviate hepatic inflammation in MASLD models (Jin et al. 2025; Ma et al. 2007).”
From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Jin et al. 2025
The Results (page not specified) report that WT Treg supplementation reduced liver inflammation and injury in MCD-fed MASLD mice; Figure 3 also measures TNF-α secretion by liver monocytes, though it does not establish reduced intrahepatic TNF-α signaling. The adoptive-transfer Methods describe transferring mouse-derived cells, not ex vivo-expanded Tregs. LPS appears in a monocyte-culture method, but our copy does not report that Treg transfer dampened LPS-induced hepatotoxicity. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCD73 deficiency impairs Treg survival and exacerbates MASLD progression; adoptively transferred WT Tregs, compared to CD73-knockout Tregs, enhanced intrahepatic Treg activity and reduced hepatic inflammation in MASLD.
“CD73, an ectoenzyme critical for the immunosuppressive function of Tregs (Deaglio et al. 2007; Ohta and Sitkovsky 2014), has also been implicated, as its deficiency impairs Treg survival and exacerbates MASLD progression. Adoptively transferred WT Tregs, compared to CD73-knockout Tregs, enhanced intrahepatic Treg activity and reduced hepatic inflammation in MASLD (Jin et al. 2025).”
From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Jin et al. 2025
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“Adoptively transferred WT Tregs, compared to CD73-knockout Tregs, enhanced intrahepatic Treg activity and reduced hepatic inflammation in MASLD (Jin et al. 2025).”
Kurbatova, I., Zhulai, G., Дуданова, О. П., & Topchieva, L. (2026) · Diseases · doi:10.3390/diseases14100372
- Authors
- Jin, H., Zhong, X., Zhang, C., Wu, Y., Sun, J., Wang, X., Wang, Z., Zhu, J., Jiang, Y., Du, X., Zhang, Z., Zhang, D., & Sun, G.
- Affiliations
- Capital Medical University (CN)
- Beijing Chao-Yang Hospital, Capital Medical University (CN)
- Corresponding author
- Sun, Guangyong
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2025-06
- Volume
- 96
- Pages
- 102131
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC12002957
- OpenAlex
- W4408800247
- Cited by
- 2
- References
- 42
- Citations by year
- 2026: 2
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Beijing Municipal Commission of Education (KZ202210025036)
- Beijing Natural Science Foundation (7232034)
- Beijing Municipal Administration of Hospitals (DFL20220103)
- National Natural Science Foundation of China (82370578, 82300596, 82202021, 82270606)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- CD73, regulatory T cells, non-alcoholic fatty liver disease, immune regulation, liver inflammation, choline-deficient high-fat diet, methionine-choline-deficient diet, adoptive Treg transfer, immunotherapy
- MeSH terms
- Animals, Fatty Liver, Liver, Male, Mice, Inbred C57BL, Signal Transduction, 5'-Nucleotidase, Mice, Knockout, T-Lymphocytes, Regulatory, Mice, Diet, High-Fat
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