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

A natural small molecule alleviates liver fibrosis by targeting apolipoprotein L2

  • Nat Chem Biol. 2024 Aug 5. doi: 10.1038/s41589-024-01704-3.
Lu Gan # 1,  Qiwei Jiang # 2,  Dong Huang # 1,  Xueji Wu 2,  Xinying Zhu 1,  Lei Wang 2,  Wei Xie 2,  Jialuo Huang 1,  Runzhu Fan 1,  Yihang Jing 3,  Guihua Tang 1,  Xiang David Li 3 4,  Jianping Guo 5,  Sheng Yin 6 7
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
  • 2 Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3 Greater Bay Biomedical InnoCenter, Shenzhen Bay Laboratory (SZBL), Shenzhen, China.
  • 4 Department of Chemistry, University of Hong Kong, Hong Kong, China.
  • 5 Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. guojp6@mail.sysu.edu.cn.
  • 6 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China. yinsh2@mail.sysu.edu.cn.
  • 7 State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China. yinsh2@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 39103634 DOI: 10.1038/s41589-024-01704-3
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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