CD73 promotes the immunoregulatory functions of hepatic Tregs through enzymatic and nonenzymatic pathways in MASLD development

Hua Jin; Xinjie Zhong; Chunpan Zhang; Yongle Wu; Jie Sun; Xiyu Wang; Zeyu Wang; Jingjing Zhu; Yuan Jiang; Xiaonan Du; Zihan Zhang; Dong Zhang; Guangyong Sun

Molecular Metabolism (Jun 2025)

CD73 promotes the immunoregulatory functions of hepatic Tregs through enzymatic and nonenzymatic pathways in MASLD development

Hua Jin,
Xinjie Zhong,
Chunpan Zhang,
Yongle Wu,
Jie Sun,
Xiyu Wang,
Zeyu Wang,
Jingjing Zhu,
Yuan Jiang,
Xiaonan Du,
Zihan Zhang,
Dong Zhang,
Guangyong Sun

Affiliations

Hua Jin: Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
Xinjie Zhong: Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
Chunpan Zhang: Department of Infectious Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
Yongle Wu: Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
Jie Sun: Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
Xiyu Wang: Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
Zeyu Wang: Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
Jingjing Zhu: Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
Yuan Jiang: Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
Xiaonan Du: Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
Zihan Zhang: Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
Dong Zhang: Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China
Guangyong Sun: Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Corresponding author. Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.

Journal volume & issue: Vol. 96
p. 102131

Abstract

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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.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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