Proteomics

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Natural small molecule DP combats liver fibrosis by targeting APOL2

ABSTRACT: Liver fibrosis is an urgent clinical problem without effective treatment. Herein, we conducted a high-content screening on a natural “privileged” diterpenoid library to identify a potent anti-liver fibrosis lead DP. Leveraging photoaffinity labeling approach, apolipoprotein L2 (APOL2), an ER-rich protein, was identified as the direct target of DP. APOL2 is mainly expressed in activated hepatic stellate cells (HSCs) and could activate HSCs to synthesize ECM proteins. It can be induced by TGF-β1 and be antagonized by DP. Mechanistically, upon TGF-β1stimulation, APOL2 binds ER Ca2+ pump SERCA2 to trigger ER stress, elevating its downstream PERK-HES1 axis to promote liver fibrosis, mildly dependent on the canonical TGF-β/Smad signaling. As a result, ablation of APOL2 significantly alleviated TGF-β1-stimulated HSCs activation, and abolished anti-fibrosis effect of DP. 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Lu Gan  

LAB HEAD: Sheng Yin

PROVIDER: PXD047924 | Pride | 2024-08-13

REPOSITORIES: Pride

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in-suit-HPT-vs-con.msf Msf
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A natural small molecule alleviates liver fibrosis by targeting apolipoprotein L2.

Gan Lu L   Jiang Qiwei Q   Huang Dong D   Wu Xueji X   Zhu Xinying X   Wang Lei L   Xie Wei W   Huang Jialuo J   Fan Runzhu R   Jing Yihang Y   Tang Guihua G   Li Xiang David XD   Guo Jianping J   Yin Sheng S  

Nature chemical biology 20240805

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 growt  ...[more]

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