Liver X receptor agonists in central nervous system disorders: From neuroprotection to clinical challenges

Central nervous system (CNS) disorders, which include both neurodegenerative and neuroinflammatory conditions, present significant therapeutic challenges due to their complex pathological mechanisms, limited treatment options, and difficulties in drug delivery across the blood-brain barrier (BBB). Therefore, exploring therapeutic targets capable of overcoming these obstacles is of paramount importance. The liver X receptor (LXR) plays a crucial role in lipid homeostasis, inhibition of neuroinflammation, and promotion of neurogenesis, making it a promising therapeutic target for CNS diseases. However, the potential adverse effects associated with LXR agonists, such as hepatic steatosis and hypertriglyceridemia, may hinder their future clinical application. In this review, we examine the dual roles of LXR agonists in CNS diseases, highlighting their therapeutic benefits alongside their adverse effects. To address these challenges, we propose several optimization strategies, including the development of LXRβ selective agonists, advanced nano-delivery systems, and combination therapies, with the ultimate goal of providing a theoretical foundation for future therapies centered on LXR.