RXRαmodulates hepatic stellate cell activation and liver fibrosis by targeting CaMKKβ-AMPKαaxis

被引：0

作者：

Cai, Lijun ^{[1
]}

Yin, Meimei ^{[2
]}

Peng, Shuangzhou ^{[1
]}

Lin, Fen ^{[1
]}

Lai, Liangliang ^{[1
]}

Zhang, Xindao ^{[3
]}

Xie, Lei ^{[1
]}

Wang, Chuanying ^{[1
]}

Zhou, Huiying ^{[1
]}

Zhan, Yunfeng ^{[1
]}

Alitongbieke, Gulimiran ^{[1
]}

Lian, Baohuan ^{[3
]}

Su, Zhibin ^{[3
]}

Liu, Tenghui ^{[1
]}

Zhou, Yuqi ^{[3
]}

Li, Zongxi ^{[1
]}

Chen, Xiaohui ^{[1
]}

Zhao, Qi ^{[1
]}

Deng, Ting ^{[1
]}

Chen, Lulu ^{[1
]}

Su, Jingwei ^{[4
]}

Sheng, Luoyan

Su, Ying ^{[3
]}

Zhang, Ling-Juan ^{[2
]}

Jiang, Fu-Quan ^{[1
]}

Zhang, Xiao-Kun ^{[1
]}

机构：

[1] Xiamen Univ, Sch Pharmaceut Sci, Fujian Prov Key Lab Innovat Drug Target Res, Xiamen 361102, Peoples R China

[2] Xiamen Univ, Sch Pharmaceut Sci, State Key Lab Cellular Stress Biol, Xiamen 361102, Peoples R China

[3] NucMito Pharmaceut Co Ltd, Xiamen 361101, Peoples R China

[4] Qinghai Minzu Univ, Coll Pharm, Xining 810007, Peoples R China

来源：

ACTA PHARMACEUTICA SINICA B | 2025年 / 15卷 / 07期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

K-80003; RXRa; AMPKa; CaMKK/3; HSCs; Liver fibrosis; Phase separation; Mitophagy; RETINOID-X-RECEPTOR; NUCLEAR RECEPTORS; PROTEIN-KINASE; INTERDOMAIN COMMUNICATION; HORMONE-RECEPTORS; THYROID-HORMONE; LIGAND-BINDING; ACID; MECHANISMS; DISEASE;

D O I：

10.1016/j.apsb.2025.05.023

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRa), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRa exerts its effects by modulating calcium/calmodulin-dependent proIn addition, we demonstrate that K-80003, which binds RXRa by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl4 and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKa activation, promotsates with CaMKK,6 and AMPKa via a two-phase process. The formation of RXRa condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKK,6. Our results reveal a crucial role of RXRa in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRa modulators hold promise as therapeutic agents for fibrosis-related diseases.

引用

页码：3611 / 3631

页数：21

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