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