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

作者：Lijun Cai, Meimei Yin, Shuangzhou Peng, Lin Fen, Li Lai, Xindao Zhang, 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, Xiao-kun Zhang · 发表于：Acta Pharmaceutica Sinica B · 年份：2025 · DOI：10.1016/j.apsb.2025.05.023 · 被引用次数：12 · 研究领域：Liver Disease Diagnosis and Treatment、Endoplasmic Reticulum Stress and Disease、Liver physiology and pathology

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 (RXR α ), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXR α exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKK β )-mediated activation of AMP-activated protein kinase-alpha (AMPK α ). In addition, we demonstrate that K-80003, which binds RXR α by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl 4 and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPK α activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPK α by inducing RXR α to form condensates with CaMKK β and AMPK α via a two-phase process. The formation of RXR α condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKK β . Our results reveal a crucial role of RXR α in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXR α modulators hold promise as therapeutic agents for fibrosis-related diseases.