Wang Junqi, Wang Huan, Yang Wenting, Zhao Dianyuan, Liu Di, Tang Li, Chen Xiao-Ping
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, PR China.; State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing. Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing 102206, PR China; Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410008, Hunan, PR China.
State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing. Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing 102206, PR China.
Int Immunopharmacol. 2025 May 8;154:114554. doi: 10.1016/j.intimp.2025.114554. Epub 2025 Apr 4.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly concerning global health issue characterized by pronounced hepatic steatosis and liver fibrosis. Hepatic monocyte-derived macrophages (MDMs) are crucial in the pathogenesis of liver fibrosis under MASLD. Nevertheless, the precise functions of MDMs and the underlying mechanisms governing their differentiation remain inadequately elucidated. In this study, we revealed an orchestrator of this process: Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB), one of the characteristic genes of MDMs. Notably, myeloid-specific Gpnmb-knockout contributed to the retention of resident Kupffer cells (KCs) and rerouted monocyte differentiation towards a monocyte-derived macrophage subset that occupies the Kupffer cell niche (MoKC subset, resembling resident KCs), thereby impeding the formation of hepatic lipid-associated macrophages (LAMs). This transition has a profound impact, manifested in significantly reduced steatosis and modestly decreased liver fibrosis in myeloid-specific Gpnmb-knockout mice. In conclusion, our research clarifies the complex interactions between Gpnmb and MDMs and underscores the therapeutic potential of targeting Gpnmb within MDMs to manage MASLD.
代谢功能障碍相关脂肪性肝病（MASLD）是一个日益引起全球关注的健康问题，其特征为明显的肝脏脂肪变性和肝纤维化。肝脏单核细胞衍生的巨噬细胞（MDM）在MASLD相关肝纤维化的发病机制中起关键作用。然而，MDM的确切功能及其分化的潜在机制仍未得到充分阐明。在本研究中，我们揭示了这一过程的一个协调因子：糖蛋白非转移性黑色素瘤蛋白B（GPNMB），它是MDM的特征基因之一。值得注意的是，髓系特异性Gpnmb基因敲除导致驻留库普弗细胞（KC）的保留，并使单核细胞分化重新导向占据库普弗细胞生态位的单核细胞衍生巨噬细胞亚群（MoKC亚群，类似于驻留KC），从而阻碍肝脏脂质相关巨噬细胞（LAM）的形成。这种转变产生了深远影响，表现为髓系特异性Gpnmb基因敲除小鼠的脂肪变性显著减轻，肝纤维化略有减轻。总之，我们的研究阐明了Gpnmb与MDM之间的复杂相互作用，并强调了以MDM中的Gpnmb为靶点治疗MASLD的潜力。
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