Exercise-induced adipokine Nrg4 alleviates MASLD by disrupting hepatic cGAS-STING signaling.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-01-30 DOI:10.1016/j.celrep.2025.115251

Min Chen, Yang Li, Jie-Ying Zhu, Wang-Jing Mu, Hong-Yang Luo, Lin-Jing Yan, Shan Li, Ruo-Ying Li, Meng-Ting Yin, Xin Li, Hu-Min Chen, Liang Guo

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引用次数: 0

Abstract

Exercise is an effective non-pharmacological strategy for ameliorating metabolic dysfunction-associated steatotic liver disease (MASLD). Neuregulin-4 (Nrg4) is an adipokine with a potential role in metabolic homeostasis. Previous findings have shown that Nrg4 is upregulated by exercise and that Nrg4 reduces hepatic steatosis, but the underlying mechanism is not fully understood. Here, we show that adipose Nrg4 is transactivated by Pparγ in response to exercise in mice. Adeno-associated virus (AAV)-mediated knockdown of adipose Nrg4 as well as hepatocyte-specific knockout of Erbb4 (Nrg4 receptor) impair exercise-mediated alleviation of MASLD in mice. Conversely, AAV-mediated overexpression of adipose Nrg4 mitigates MASLD in mice in synergy with exercise. Mechanistically, Nrg4/Erbb4/AKT signaling promotes cyclic guanosine monophosphate-AMP synthase (cGAS) phosphorylation to blunt its enzyme activity, thereby inhibiting cGAS-STING pathway-mediated inflammation and steatosis in hepatocytes. Thus, Nrg4 functions as an exercise-induced adipokine that participates in adipose-liver tissue communication to counteract MASLD.

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.