A natural small molecule alleviates liver fibrosis by targeting apolipoprotein L2.

IF 12.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Nature chemical biology Pub Date : 2024-08-05 DOI:10.1038/s41589-024-01704-3

Lu Gan, Qiwei Jiang, Dong Huang, Xueji Wu, Xinying Zhu, Lei Wang, Wei Xie, Jialuo Huang, Runzhu Fan, Yihang Jing, Guihua Tang, Xiang David Li, Jianping Guo, Sheng Yin

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Abstract

Liver fibrosis is an urgent clinical problem without effective therapies. Here we conducted a high-content screening on a natural Euphorbiaceae diterpenoid library to identify a potent anti-liver fibrosis lead, 12-deoxyphorbol 13-palmitate (DP). Leveraging a photo-affinity labeling approach, apolipoprotein L2 (APOL2), an endoplasmic reticulum (ER)-rich protein, was identified as the direct target of DP. Mechanistically, APOL2 is induced in activated hepatic stellate cells upon transforming growth factor-β1 (TGF-β1) stimulation, which then binds to sarcoplasmic/ER calcium ATPase 2 (SERCA2) to trigger ER stress and elevate its downstream protein kinase R-like ER kinase (PERK)-hairy and enhancer of split 1 (HES1) axis, ultimately promoting liver fibrosis. As a result, targeting APOL2 by DP or ablation of APOL2 significantly impairs APOL2-SERCA2-PERK-HES1 signaling and mitigates fibrosis progression. Our findings not only define APOL2 as a novel therapeutic target for liver fibrosis but also highlight DP as a promising lead for treatment of this symptom.

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一种天然小分子通过靶向载脂蛋白 L2 缓解肝纤维化。

肝纤维化是一个亟待解决而又缺乏有效疗法的临床问题。在此，我们对天然大戟科植物二萜类化合物库进行了高含量筛选，以确定一种有效的抗肝脏纤维化先导化合物--12-脱氧樟脑醇 13-棕榈酸酯（DP）。利用光亲和性标记方法，脂蛋白 L2（APOL2）这种富含内质网（ER）的蛋白质被确定为 DP 的直接靶标。从机理上讲，当转化生长因子-β1（TGF-β1）刺激活化的肝星状细胞时，APOL2会被诱导，然后与肌浆/ER钙ATP酶2（SERCA2）结合，引发ER应激，并使其下游的蛋白激酶R样ER激酶（PERK）-毛发和增强分裂1（HES1）轴升高，最终促进肝纤维化。因此，通过DP或消融APOL2靶向APOL2可显著损害APOL2-SERCA2-PERK-HES1信号传导，缓解肝纤维化进展。我们的研究结果不仅将APOL2定义为肝纤维化的新型治疗靶点，还强调了DP是治疗肝纤维化的一种有前景的方法。

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来源期刊

Nature chemical biology 生物-生化与分子生物学

CiteScore

23.90

自引率

1.40%

发文量

238

审稿时长

12 months

期刊介绍： Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.

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