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.

OBJECTIVE：To provide technical met hods for marketing authorization holder （MAH）to effectively use the data of adverse drug reaction （ADR），actively monitor and control the production quality risk ，and carry out drug production risk management. METHODS ：Through establishing three-dimensional risk matrix and risk trend model ，the risk early warning system of MAH production line based on ADR report data is designed and developed ；the main functions of the system were applied and analyzed according to the actual ADR report data of a certain company. RESULTS ：MAH production line risk warning system was established preliminarily. The main framework included data source and and processing module ，model construction module （three-dimensional matrix model included possibility index ，severity index and sensitivity index ，risk trend model was set according to the principle of product production batch number preparation ），and result output & analysis module. Five major functional modules included system configuratio ，production line signal detection ，visual statistical early warning ，ADR report management and standard data management. The application and analysis of ADR report data of a certain company showed that the system could realize detection and warning of the company ’s production line risk ，which intuitively reflected its high-risk production lines ，varieties and batch numbers. It was consistent wit h the actual safety sit uation of the company ’s varieties. CONCLUSIONS：The system can help MAH make use of ADR report data to actively monitor drug production quality risks in a timely manner ，investigate risk factors for high-risk production lines ， high-risk varieties and high-risk batch numbers，and assist in decision-making on the direction of risk investigation.