RXR modulates hepatic stellate cell activation and liver fibrosis by targeting CaMKK-AMPK axis.

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