RXRα modulates hepatic stellate cell activation and liver fibrosis by targeting CaMKKβ-AMPKα axis.

Lijun CAI; Meimei YIN; Shuangzhou PENG; Fen LIN; Liangliang LAI; Xindao ZHANG; Lei XIE; Chuanying WANG; Huiying ZHOU; Yunfeng ZHAN; Gulimiran ALITONGBIEKE; Baohuan LIAN; Zhibin SU; Tenghui LIU; Yuqi ZHOU; Zongxi LI; Xiaohui CHEN; Qi ZHAO; Ting DENG; Lulu CHEN; Jingwei SU; Luoyan SHENG; Ying SU; Ling-Juan ZHANG; Fu-Quan JIANG; Xiao-Kun ZHANG

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RXRα modulates hepatic stellate cell activation and liver fibrosis by targeting CaMKKβ-AMPKα axis.

Author: Lijun CAI ¹ ; Meimei YIN ² ; Shuangzhou PENG ¹ ; Fen LIN ¹ ; Liangliang LAI ¹ ; Xindao ZHANG ³ ; Lei XIE ¹ ; Chuanying WANG ¹ ; Huiying ZHOU ¹ ; Yunfeng ZHAN ¹ ; Gulimiran ALITONGBIEKE ¹ ; Baohuan LIAN ³ ; Zhibin SU ³ ; Tenghui LIU ¹ ; Yuqi ZHOU ³ ; Zongxi LI ¹ ; Xiaohui CHEN ¹ ; Qi ZHAO ¹ ; Ting DENG ¹ ; Lulu CHEN ¹ ; Jingwei SU ⁴ ; Luoyan SHENG ¹ ; Ying SU ³ ; Ling-Juan ZHANG ² ; Fu-Quan JIANG ¹ ; Xiao-Kun ZHANG ¹
Author Information

1. School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361102, China.
2. State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
3. NucMito Pharmaceuticals Co., Ltd., Xiamen 361101, China.
4. College of Pharmacy, Qinghai Minzu University, Xining 810007, China.
Publication Type:Journal Article
Keywords: AMPKα; CaMKKβ; HSCs; K-80003; Liver fibrosis; Mitophagy; Phase separation; RXRα
From: Acta Pharmaceutica Sinica B 2025;15(7):3611-3631
CountryChina
Language:English
Abstract: 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 (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα 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 AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.