MIF-ACKR3通过损害癌症恶病质中的脂肪生成导致不可逆的脂肪减少

IF 27.7 1区生物学 Q1 CELL BIOLOGY

Cell metabolism Pub Date : 2025-02-27 DOI:10.1016/j.cmet.2025.01.018

Qionghua Cui, Shijin Li, Xidan Liu, Jie Liu, Wenxin Chen, Ye Sheng, Peng Xie, Li Jin, Fanxin Zeng, Fengxiang Lv, Xinli Hu, Rui-Ping Xiao

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引用次数: 0

摘要

运动和癌症都能导致脂肪组织萎缩。然而，只有癌症相关的体重减轻，即恶病质，以严重的脂肪炎症和纤维化为特征。在这里，我们发现肿瘤分泌的巨噬细胞迁移抑制因子（MIF）是使脂肪干细胞和祖细胞（ASPCs）向促炎和促纤维化方向分化的主要驱动因素，在癌症恶病质中降低脂肪生成能力。相反，运动后循环MIF适度减少。在机制上，非典型趋化因子受体3 （ACKR3）在ASPCs中作为主要的MIF受体介导其病理作用。通过肿瘤细胞中的基因消融或药物阻断抑制MIF，以及aspc特异性Ackr3缺陷，可显著缓解肿瘤诱导的恶病质。这些发现揭示了MIF-ACKR3信号作为肿瘤和恶病质表现之间的关键联系，为癌症恶病质提供了一个有希望的治疗靶点。

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MIF-ACKR3 causes irreversible fat loss by impairing adipogenesis in cancer cachexia

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MIF-ACKR3 causes irreversible fat loss by impairing adipogenesis in cancer cachexia

Both exercise and cancer can cause adipose tissue shrinkage. However, only cancer-associated weight loss, namely cachexia, is characterized by profound adipose inflammation and fibrosis. Here, we identified tumor-secreted macrophage migration inhibitory factor (MIF) as a major driver that skews the differentiation of adipose stem and progenitor cells (ASPCs) toward a pro-inflammatory and pro-fibrogenic direction, with reduced adipogenic capacity in cancer cachexia. By contrast, circulating MIF is moderately reduced after exercise. Mechanistically, atypical chemokine receptor 3 (ACKR3) in ASPCs serves as the predominant MIF receptor mediating its pathological effects. Inhibition of MIF by gene ablation in tumor cells or pharmacological blockade, as well as ASPC-specific Ackr3 deficiency, markedly alleviates tumor-induced cachexia. These findings unveil MIF-ACKR3 signaling as a critical link between tumors and cachectic manifestations, providing a promising therapeutic target for cancer cachexia.

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来源期刊

Cell metabolism 生物-内分泌学与代谢

CiteScore

48.60

自引率

1.40%

发文量

173

审稿时长

2.5 months

期刊介绍： Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others. Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.