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